Nicotinamide Derivatives Useful as p38 Inhibitors

ABSTRACT

Compounds of formula (I):  
                 
are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.

This invention relates to novel compounds and their use aspharmaceuticals, particularly as p38 kinase inhibitors, for thetreatment of conditions or disease states mediated by p38 kinaseactivity or mediated by cytokines produced by the activity of p38kinase.

We have now found a group of novel compounds that are inhibitors of p38kinase.

According to the invention there is provided a compound of formula (I):

wherein

R¹ is selected from hydrogen, C₁₋₆alkyl optionally substituted by up tothree groups selected from C₁₋₆alkoxy, halogen and hydroxy, C₂₋₆alkenyl,C₃₋₇cycloalkyl optionally substituted by one or more C₁₋₆alkyl groups,phenyl optionally substituted by up to three groups selected from R⁵ andR⁶, and heteroaryl optionally substituted by up to three groups selectedfrom R⁵ and R⁶,

R² is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups,

or (CH₂)_(m)R¹ and R², together with the nitrogen atom to which they arebound, form a four- to six-membered heterocyclic ring optionallysubstituted by up to three C₁₋₆alkyl groups;

R³ is chloro or methyl;

R⁴ is the group —NH—CO—R⁷ or —CO—NH—(CH₂)_(q)—R⁸;

R⁵ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰,—NHCOR¹⁰, —SO₂NHR⁹, —(CH₂)_(s)NHSO₂R¹⁰, halogen, CN, OH,—(CH₂)_(s)NR¹¹R¹², and trifluoromethyl;

R⁶ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl and—(CH₂)_(s)NR¹¹R¹²;

R⁷ is selected from hydrogen, C₁₋₆alkyl, —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, trifluoromethyl,—(CH₂)_(r)heteroaryl optionally substituted by R¹³ and/or R¹⁴, and—(CH₂)_(r)phenyl optionally substituted by R¹³ and/or R¹⁴;

R⁸ is selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl optionallysubstituted by one or more C₁₋₆alkyl groups, CONHR⁹, phenyl optionallysubstituted by R¹³ and/or R¹⁴, and heteroaryl optionally substituted byR¹³ and/or R¹⁴;

R⁹ and R¹⁰ are each independently selected from hydrogen and C₁₋₆alkyl,

or R⁹ and R¹⁰, together with the nitrogen atom to which they are bound,form a five- to six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups;

R¹¹ is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups,

R¹² is selected from hydrogen and C₁₋₆alkyl,

or R¹¹ and R¹², together with the nitrogen atom to which they are bound,form a five or six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵;

R¹³ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰,—NHCOR¹⁰, halogen, CN, —(CH₂)_(s)NR¹¹R¹², trifluoromethyl, phenyloptionally substituted by one or more R¹⁴ groups and heteroaryloptionally substituted by one or more R¹⁴ groups;

R¹⁴ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl and—NR¹¹R¹²;

R¹⁵ is selected from hydrogen and methyl;

X and Y are each independently selected from hydrogen, methyl andhalogen;

Z is halogen;

m is selected from 0, 1, 2, 3 and 4, wherein each carbon atom of theresulting carbon chain may be optionally substituted with up to twogroups selected independently from C₁₋₆alkyl and halogen;

n is selected from 0, 1 and 2;

q is selected from 0, 1 and 2;

r is selected from 0 and 1; and

s is selected from 0, 1, 2 and 3.

According to a further embodiment of the invention there is provided acompound of formula (IA):

wherein R¹, R², R³, R⁴ and m are as defined above.

According to one embodiment of the present invention, R¹ is selectedfrom hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl optionally substitutedby R⁵ and/or R⁶, and heteroaryl optionally substituted by R⁵ and/or R⁶,and R² is selected from hydrogen, C₁₋₆alkyl and—(CH₂)_(q)—C₃₋₇cycloalkyl.

In a preferred embodiment, R¹ is selected from C₁₋₆alkyl, for examplemethyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 1-ethyl-1-methyl-propyl, n-butyl, isobutyl,3-methylbutyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl,2-pentyl or 1-methylpentyl, optionally substituted by up to three groupsselected from C₁₋₆alkoxy, in particular C₁₋₄alkoxy groups such methoxyor t-butoxy, halogen, in particular fluorine, and hydroxy; C₂₋₆alkenyl,for example C₄₋₆alkenyl such as 3-methylbut-2-enyl or1,1-dimethylbut-2-enyl; C₃₋₇cycloalkyl optionally substituted by one ormore C₁₋₆alkyl groups, for example cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl, in particular cyclopropyl, optionally substituted by oneor two C₁₋₄alkyl groups such as methyl or ethyl; phenyl optionallysubstituted by up to three groups selected from R⁵ and R⁶, for examplephenyl optionally substituted by up to three substituents, for exampleone or two substituents, such as C₁₋₄alkyl, in particular methyl,C₁₋₄alkoxy, in particular methoxy, halogen, in particular fluorine orchlorine, trifluoromethyl, —(CH₂)_(s)NR¹¹R¹² or —(CH₂)_(s)NHSO₂R¹⁰,located on any position on the ring; heteroaryl optionally substitutedby tip to three groups selected from R⁵ and R⁶, for example heteroaryloptionally substituted by one or two substituents, in particular a5-membered heteroaryl such as furyl, thienyl or thiazolyl optionallysubstituted by C₁₋₄alkyl, in particular methyl. In a particularlypreferred embodiment, R¹ is C₁₋₆alkyl, for example C₂₋₅ alkyl, such asethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, n-butyl, isobutyl, 3-methylbutyl or 2-pentyl.

In another preferred embodiment, R¹ is selected from C₃₋₇cycloalkyl,phenyl optionally substituted by R⁵ and/or R⁶, and heteroaryl optionallysubstituted by R⁵ and/or R⁶. In a more preferred embodiment, R¹ isselected from C₃₋₆cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, in particular cyclopropyl, and phenyloptionally substituted by R⁵ and/or R⁶. The phenyl may be optionallysubstituted by one or two substituents, located on any position on thephenyl ring. Preferred substituents for the phenyl include C₁₋₄alkoxy,in particular methoxy, —(CH₂)_(s)NR¹¹R¹², and —(CH₂)_(s)NHSO₂R¹⁰.

In another preferred embodiment, R¹ is selected from C₁₋₆alkyl, forexample n-propyl, 1-methylpropyl, isobutyl, 3-methylbutyl or2,2-dimethylpropyl, and C₃₋₇cycloalkyl optionally substituted by one ormore C₁₋₆alkyl groups, for example cyclopropyl optionally substituted byone or two methyl groups.

In a further preferred embodiment, R¹ is selected from C₁₋₆alkyl, forexample methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl,1-ethyl-1-methyl-propyl, n-butyl, isobutyl, 1,1-dimethylbutyl,1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1-methylpentyl,optionally substituted by up to three groups selected from C₁₋₆alkoxy,in particular C₁₋₄alkoxy groups such methoxy or t-butoxy, halogen, inparticular fluorine, and hydroxy; C₂₋₆alkenyl, for example C₄₋₆alkenylsuch as 3-methylbut-2-enyl or 1,1-dimethylbut-2-enyl; C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, for example,cyclopropyl, cyclopentyl or cyclohexyl, optionally substituted by one ortwo ethyl groups; phenyl optionally substituted by up to three groupsselected from R⁵ and R⁶, for example phenyl optionally substituted by upto three substituents such as C₁₋₄alkyl, in particular methyl,C₁₋₄alkoxy, in particular methoxy, halogen, in particular fluorine orchlorine and trifluoromethyl, located on any position on the ring;heteroaryl optionally substituted by up to three groups selected from R⁵and R⁶, in particular a 5-membered heteroaryl such as furyl, thienyl orthiazolyl optionally substituted by C₁₋₄alkyl, in particular methyl.

In a preferred embodiment, R² is selected from hydrogen; C₁₋₄alkyl, inparticular methyl, ethyl, isopropyl or isobutyl; and—(CH₂)_(q)—C₃₋₆cycloalkyl, in particular cyclopropyl, —CH₂-cyclopentyl,—(CH₂)₂-cyclopentyl or cyclohexyl.

In another preferred embodiment, R² is selected from hydrogen, C₁₋₄alkyland —CH₂-cyclopropyl. More preferably R² is hydrogen.

In a further preferred embodiment, (CH₂)_(m)R¹ and R², together with thenitrogen atom to which they are bound, form a four- to six-memberedheterocyclic ring optionally substituted by up to three C₁₋₆alkylgroups, in particular an azetidinyl, pyrrolidinyl or piperidinyl ringoptionally substituted by one or two methyl, ethyl or propyl groups.

In a preferred embodiment, R³ is methyl.

In a preferred embodiment, R⁴ is the group —CO—NH—(CH₂)_(q)—R⁸.

In one embodiment of the present invention, R⁵ is selected fromC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰,—SO₂NHR⁹, —(CH₂)_(s)NHSO₂R¹⁰, halogen, CN, OH, —(CH₂)_(s)NR¹¹R¹², andtrifluoromethyl.

In a preferred embodiment, R⁵ is selected from C₁₋₄alkyl, in particularmethyl; C₁₋₄alkoxy, in particular methoxy; —(CH₂)_(s)NHSO₂R¹⁰; halogen,in particular chlorine or fluorine; —(CH₂)_(s)NR¹¹R¹²; andtrifluoromethyl.

In another preferred embodiment, R⁵ is selected from C₁₋₄alkoxy, inparticular methoxy, —(CH₂)_(s)NR¹¹R¹², and —(CH₂)_(s)NHSO₂R¹⁰.

In a further preferred embodiment, R⁵ is selected from C₁₋₄alkyl, inparticular methyl; C₁₋₄alkoxy, in particular methoxy; halogen, inparticular chlorine or fluorine; and trifluoromethyl.

In a preferred embodiment, R⁶ is selected from C₁₋₄alkyl, in particularmethyl, ethyl or propyl; C₁₋₄alkoxy, in particular methoxy; halogen, inparticular chlorine or fluorine; and trifluoromethyl.

In a further preferred embodiment, R⁶ is C₁₋₄alkoxy, in particularmethoxy.

In one embodiment of the present invention, R⁷ is selected fromhydrogen, C₁₋₆alkyl, —(CH₂)_(q)—C₃₋₇cycloalkyl, trifluoromethyl,—(CH₂)_(r)heteroaryl optionally substituted by R¹³ and/or R¹⁴, and—(CH₂)_(r)phenyl optionally substituted by R¹³ and/or R¹⁴.

In a preferred embodiment, R⁷ is selected from C₁₋₆alkyl,—(CH₂)_(q)—C₃₋₇cycloalkyl, trifluoromethyl, —(CH₂)_(r)heteroaryloptionally substituted by R¹³ and/or R¹⁴, and —(CH₂)_(r)phenyloptionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand/or heteroaryl optionally substituted by one or more R¹⁴ groups. Inanother preferred embodiment, R⁷ is selected from C₁₋₄alkyl,—(CH₂)_(q)—C₃₋₆cycloalkyl, trifluoromethyl, —(CH₂)_(r)heteroaryloptionally substituted by R¹³ and/or R¹⁴, and —(CH₂)_(r)phenyloptionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand/or heteroaryl optionally substituted by one or more R¹⁴ groups. In amore preferred embodiment, R⁷ is —(CH₂)_(r)heteroaryl optionallysubstituted by R¹³ and/or R¹⁴, in particular a five or six-memberedheteroaryl containing at least one heteroatom selected from oxygen,nitrogen and sulfur, for example, pyridinyl optionally substituted by—NR¹¹R¹², furyl or thiophenyl.

In one embodiment of the present invention, R⁸ is selected fromhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, CONHR⁹, phenyl optionallysubstituted by R¹³ and/or R¹⁴, and heteroaryl optionally substituted byR¹³ and/or R¹⁴

In a preferred embodiment, R⁸ is selected from C₃₋₇cycloalkyl, CONHR⁹,heteroaryl optionally substituted by R¹³ and/or R¹⁴, and phenyloptionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand/or heteroaryl optionally substituted by one or more R¹⁴ groups. Inanother preferred embodiment, R⁸ is selected from C₃₋₇cycloalkyl,heteroaryl optionally substituted by R¹³ and/or R¹⁴, and phenyloptionally substituted C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl,—CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN, trifluoromethyl, phenyl optionallysubstituted by one or more R¹⁴ groups and/or heteroaryl optionallysubstituted by one or more R¹⁴ groups. In a more preferred embodiment,R⁸ is selected from C₃₋₆cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, in particular cyclopropyl, heteroaryloptionally substituted by R¹³ and/or R¹⁴, in particular a five orsix-membered heteroaryl containing at least one heteroatom selected fromnitrogen and sulfur, for example, thiazolyl or thiadiazolyl, and phenyloptionally substituted by heteroaryl. In a particularly preferredembodiment, R⁸ is selected from C₃₋₆cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl.

In a preferred embodiment, R⁹ is selected from hydrogen and C₁₋₄alkyl.

In a preferred embodiment, R¹⁰ is selected from hydrogen and C₁₋₄alkyl,in particular methyl.

In one embodiment, R¹¹ is selected from hydrogen, C₁₋₆alkyl and—(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by C₁₋₆alkyl.

In a preferred embodiment, R¹¹ and R¹², together with the nitrogen atomto which they are bound, form a five or six-membered heterocyclic ringoptionally farther containing one additional heteroatom N—R¹⁵.

In one embodiment of the present invention, R¹³ is selected fromC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰,halogen, CN, —(CH₂)_(s)NR¹¹R¹², trifluoromethyl, phenyl optionallysubstituted by one or more R¹⁴ groups and heteroaryl optionallysubstituted by one or more R¹⁴ groups;

In a preferred embodiment, R¹³ is selected from C₁₋₄alkyl, in particularmethyl, C₁₋₄alkoxy, in particular methoxy, halogen, —(CH₂),NR¹¹R¹²,phenyl optionally substituted by one or more R¹⁴ groups and heteroaryloptionally substituted by one or more R¹⁴ groups. In a more preferredembodiment, R¹³ is selected from —(CH₂)_(s)NR¹¹R¹² and heteroaryloptionally substituted by one or more R¹⁴ groups, in particular a fiveor six-membered heteroaryl containing at least one nitrogen atom, forexample, pyridyl.

In a preferred embodiment R¹⁴ is selected from from C₁₋₄alkyl, inparticular methyl, C₁₋₄alkoxy, in particular methoxy, and —NR¹¹R¹².

In a preferred embodiment, R¹⁵ is methyl.

In a preferred embodiment, X and Y are each independently selected fromhydrogen, chlorine and fluorine. In a further preferred embodiment, X isfluorine. In another preferred embodiment, Y is hydrogen.

In a preferred embodiment, Z is fluorine.

In one embodiment of the present invention, m is selected from 0, 1, 2,3 and 4. In another embodiment of the present invention, m is selectedfrom 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbonchain may be optionally substituted with up to two groups selectedindependently from C₁₋₆alkyl.

In a preferred embodiment, m is selected from 0, 1, 2 and 3. In afurther preferred embodiment, m is selected from 0, 1 and 2, inparticular 0 and 1. When the carbon chain of m is substituted, thesesubstituents are preferably one or two methyl groups or fluorine atoms.In one embodiment, the substituents are preferably one or two methylgroups. In another embodiment, the substituents are preferably one ortwo fluorine atoms.

In a preferred embodiment, n is selected from 0 and 1. In particular, nis 0.

In a preferred embodiment, q is selected from 0 and 1. In particular, qis 0.

In a preferred embodiment, r is 0.

In a preferred embodiment, s is selected from 0 and 1.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Particular compounds according to the invention include those mentionedin the Examples. Specific examples which may be mentioned include:

-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-cyclopropylethyl)-nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2-methylpropyl)-nicotinamide;    and-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(1-methylpropyl)-nicotinamide.

Futher specific examples which may be mentioned include:

-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutylmethyl-nicotinamide;-   6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-cyclobutyl-nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,4,5-trifluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,5-difluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3,4-difluorobenzyl)nicotinamide;-   N-(3-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(4-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(3-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3    -fluoro-2-methylphenyl}nicotinamide;-   N-(2-chloro-3,6-difluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3-difluoro-4-methylbenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3,5-trifluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3    -fluoro-4-methylbenzyl)nicotinamide;-   N-(5-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   N-(2-chlorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(4-fluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,3,4-trifluorobenzyl)nicotinamide;-   N-benzyl-6-{-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[3-(trifluoromethyl)benzyl]nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylbutyl)nicotinamide;-   N-(4-chloro-2-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[4-(trifluoromethyl)benzyl]nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(5-methyl-2-furyl)methyl]nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}—N-(2,3-difluorobenzyl)nicotinamide;-   N-(3-chloro-4-fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(4-methylbenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(3-methylthien-2-yl)methyl]nicotinamide;-   N-(3-chloro-2,6-difluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethyl-1-methylpropyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2-fluorobenzyl)nicotinamide;-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(tert-pentyl)nicotinamide;    and-   6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(3-methylbenzyl)nicotinamide.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl and t-butyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl, isopropyl or t-butyl. The saidalkyl groups may be optionally substituted with one or more fluorineatoms for example, trifluoromethyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl,propenyl, 3-methylbut-2-enyl and 1,1-dimethylbut-2-enyl.

As used herein, the term “alkoxy” refers to a straight or branched chainalkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.A C₁₋₄alkoxy group is preferred, for example methoxy or ethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms whichmay optionally contain up to one double bond. For example,C₃₋₇cycloalkyl means a non-aromatic ring containing at least three, andat most seven, ring carbon atoms. Examples of “cycloalkyl” as usedherein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₃₋₆cycloalkyl group ispreferred, for example, cyclopropyl, cyclopentyl or cyclohexyl. The saidcycloalkyl groups may be optionally substituted with one or moreC₁₋₆alkyl groups, for example one or two methyl groups. In oneembodiment, the cycloalkyl groups may be optionally substituted by up tofour C₁₋₆alkyl groups, for example one or two C₁₋₆alkyl groups, inparticular one or two C₁₋₄alkyl groups such as methyl or ethyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to amonocyclic five- to seven-membered unsaturated hydrocarbon ringcontaining at least one heteroatom independently selected from oxygen,nitrogen and sulfur. Preferably, the heteroaryl ring has five or sixring atoms. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl andtriazinyl. The said ring may be optionally substituted by one or moresubstituents independently selected from C₁₋₆alkyl and oxy.

As used herein, the terms “heterocyclic ring” or “heterocyclyl” refer toa monocyclic three- to seven-membered saturated hydrocarbon ringcontaining at least one heteroatom independently selected from oxygen,nitrogen and sulfur. Preferably, the heterocyclyl ring has five or sixring atoms. Examples of heterocyclyl groups include, but are not limitedto, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,morpholino, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholino.The said ring may be optionally substituted by one or more substituentsindependently selected from C₁₋₆alkyl and oxy.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine orchlorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include water, ethanol and aceticacid. All such solvates are included within the scope of the presentinvention.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

Salts of the compounds of the present invention are also encompassedwithin the scope of the invention and may, for example, comprise acidaddition salts resulting from reaction of an acid with a basic nitrogenatom present in a compound of formula (I).

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention.Representative salts include the following salts: Acetate,Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate,Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucainine, Oxalate, Pamoate (Embonate), Palmitate,Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium,Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate,Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. Othersalts which are not pharmaceutically acceptable may be useful in thepreparation of compounds of this invention and these form a furtheraspect of the invention.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

A compound of formula (I) may be prepared by reacting a compound of (II)

in which R¹, R², Z, m and n are as hereinbefore defined and W ishalogen, in particular bromine or chlorine, with a compound of formula(III)

in which R³, R⁴, X and Y are as hereinbefore defined, in the presence ofa catalyst, for example tetrakis(triphenylphosphine)palladium.

A compound of formula (II) may readily be prepared from a correspondingacid compound of formula (IV)

in which Z, W and n are as hereinbefore defined, by converting the acidto an activated form of the acid, for example the acid chloride, bytreatment with, for example, thionyl chloride, and then reacting theactivated acid thus formed with an amine compound of formula (V)

in which R¹, R² and m are as hereinbefore defined, under amide formingconditions.

Suitable amide forming conditions are well known in the art and includetreating a solution of the acid of formula (IV), or the activated formthereof, in for example acetone or dichloromethane, with an amine offormula (V) in the presence of sodium carbonate.

A compound of formula (III) may be prepared by reacting a compound offormula (VI)

in which R³, R⁴, X and Y are as hereinbefore defined and hal is halogen,in particular iodine, with bis(pinnacolato)diboron, PdCl₂dppf andpotassium acetate in a solvent such as DMF.

Alternatively, when R⁴ is —CO—NH—(CH₂)_(q)—R⁸, a compound of formula(III) may be prepared by reacting an acid compound of formula (VII)

in which R³, hal, X and Y are as hereinbefore defined, withbis(pinnacolato)diboron, PdCl₂dppf and potassium acetate in a solventsuch as DMF, and then forming an amide by reaction with an aminecompound of formula (V) as hereinbefore defined.

A compound of formula (I) may also be prepared by reacting a compound offormula (VIII)

with a compound of formula (III) as hereinbefore defined and thenreacting the acid thus formed with an amine of formula (V) ashereinbefore defined, under amide forming conditions.

Additionally, a compound of formula (I) may be prepared by reacting acompound of (II) as hereinbefore defined with a compound of formula (IX)

in which R³, R⁴, X and Y are as hereinbefore defined, in the presence ofa catalyst, for example tetrakis(triphenylphosphine)palladium.

For example, one general method for preparing the compounds of formula(I) comprises the reactions set out in Scheme 1 below.

Whilst it is possible for the compounds of the present invention to beadministered as the new chemical, the compounds of formula (I) areconveniently administered in the form of pharmaceutical compositions.Thus, in another aspect of the invention, we provide a pharmaceuticalcomposition comprising a compound of formula (I), in admixture with oneor more pharmaceutically acceptable carriers, diluents or excipients.

The compounds of formula (I) may be formulated for administration in anysuitable manner. They may, for example, be formulated for topicaladministration or administration by inhalation or, more preferably, fororal, transdermal or parenteral administration. The pharmaceuticalcomposition may be in a form such that it can effect controlled releaseof the compounds of formula (I). A particularly preferred method ofadministration, and corresponding formulation, is oral administration.

For oral administration, the pharmaceutical composition may take theform of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), pills, powders, granules, elixirs,tinctures, emulsions, solutions, syrups or suspensions prepared byconventional means with acceptable excipients.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules can be made by preparing a powder mixture as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and inultilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention can also be administered in theform of liposome emulsion delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropyhnethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Likewise, the composition may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscular,inhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

For parenteral administration, the pharmaceutical composition may begiven as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative. Alternatively for parenteraladministration the active ingredient may be in powder form forreconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively the composition may be formulated for topical application,for example in the form of ointments, creams, lotions, eye ointments,eye drops, ear drops, mouthwash, impregnated dressings and sutures andaerosols, and may contain appropriate conventional additives, including,for example, preservatives, solvents to assist drug penetration, andemollients in ointments and creams. Such topical formulations may alsocontain compatible conventional carriers, for example cream or ointmentbases, and ethanol or oleyl alcohol for lotions. Such carriers mayconstitute from about 1% to about 98% by weight of the formulation; moreusually they will constitute up to about 80% by weight of theformulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

The pharmaceutical compositions generally are administered in an amounteffective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in human is accompanied by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight. In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0. 1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the age, weightand response of the particular individual. The effectiveness of aselected actual dose can readily be determined, for example, bymeasuring clinical symptoms or standard anti-inflammatory indicia afteradministration of the selected dose. The above dosages are exemplary ofthe average case. There can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention. For conditions or disease states as are treated bythe present invention, maintaining consistent daily levels in a subjectover an extended period of time, e.g., in a maintenance regime, can beparticularly beneficial.

In another aspect, the present invention provides a compound of formula(I) for use in therapy.

The compounds of the present invention are generally inhibitors of theserine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the scribe/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrate according to the assaydescribed below.

It will be appreciated that the compounds of the invention may beselective for one or more of the isoforms of p38, for example p38α,p38β, p38γ and/or p38δ. In one embodiment, the compounds of theinvention selectively inhibit the p38α isoform. In another embodiment,the compounds of the invention selectively inhibit the p38β isoform. Ina farther embodiment, the compounds of the invention selectively inhibitthe p38α and p38β isoforms. Assays for determining the selectivity ofcompounds for the p38 isoforms are described in, for example, WO99/61426, WO 00/71535 and WO 02/46158.

It is known that p38 kinase activity can be elevated (locally orthroughout the body), p38 kinase can be incorrectly temporally active orexpressed, p38 kinase can be expressed or active in an inappropriatelocation, p38 kinase can be constitutively expressed, or p38 kinaseexpression can be erratic; similarly, cytokine production mediated byp38 kinase activity can be occurring at inappropriate times,inappropriate locations, or it can occur at detrimentally high levels.

Accordingly, the present invention provides a method for the treatmentof a condition or disease state mediated by p38 kinase activity, ormediated by cytokines produced by the activity of p38 kinase, in asubject which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I). The compound may beadministered as a single or polymorphic crystalline form or forms, anamorphous form, a single enantiomer, a racemic mixture, a singlestereoisomer, a mixture of stereoisomers, a single diastereoisomer or amixture of diastereoisomers.

The present invention also provides a method of inhibiting cytokineproduction which is mediated by p38 kinase activity in a subject, e.g. ahuman, which comprises administering to said subject in need of cytokineproduction inhibition a therapeutic, or cytokine-inhibiting, amount of acompound of the present invention. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments.

The compounds of the present invention can be administered to anysubject in need of inhibition or regulation of p38 kinase or in need ofinhibition or regulation of p38 mediated cytokine production. Inparticular, the compounds may be administered to mammals. Such mammalscan include, for example, horses, cows, sheep, pigs, mice, dogs, cats,primates such as chimpanzees, gorillas, rhesus monkeys, and, mostpreferably, humans.

Thus, the present invention provides methods of treating or reducingsymptoms in a human or animal subject suffering from, for example,rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema,allergic rhinitis, allergic conjunctivitis, adult respiratory distresssyndrome, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, silicosis, endotoxemia, toxic shocksyndrome, inflammatory bowel disease, tuberculosis, atherosclerosis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiplesclerosis, aneurism, stroke, irritable bowel syndrome, muscledegeneration, bone resorption diseases, osteoporosis, diabetes,reperfusion injury, graft vs. host reaction, allograft rejections,sepsis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to aquired immune deficiency syndrome(AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lymedisease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I).

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy and cancer including breast cancer, coloncancer, lung cancer and prostatic cancer, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I).

A farther aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease and cancer including breast cancer, colon cancer, lungcancer and prostatic cancer, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I).

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,chronic pulmonary inflammation, chronic obstructive pulmonary disease,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I).

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from any type of pain includingchronic pain, rapid onset of analgesis, neuromuscular pain, headache,cancer pain, acute and chronic inflammatory pain associated withosteoarthritis and rheumatoid arthritis, post operative inflammatorypain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia,post-hepatic neuralgia, inflammatory neuropathies and migraine painwhich comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof.

The compounds of formula (D may be employed alone or in combination withother therapeutic agents for the treatment of the above-mentionedconditions. In particular, in rheumatoid arthritis therapy, combinationwith other chemotherapeutic or antibody agents is envisaged. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of formula (I) and at least oneother pharmaceutically active agent. The compound(s) of formula (I) andthe other pharmaceutically active agent(s) may be administered togetheror separately and, when administered separately, this may occurseparately or sequentially in any order. The amounts of the compound(s)of formula (I) and the other pharmaceutically active agent(s) and therelative timings of administration will be selected in order to achievethe desired combined therapeutic effect. Examples of otherpharmaceutically active agents which may be employed in combination withcompounds of formula (I) for rheumatoid arthritis therapy include:immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone;anti-TNFα agents such as etanercept, infliximab, diacerein; tyrosinekinase inhibitors such as leflunomide; kallikein antagonists such assubreum; interleukin 11 agonists such as oprelvekin; interferon beta 1agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amyloid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

EXAMPLES

The following examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature.

LCMS was conducted on a column (3.3 cm×4.6 mm ID, 3 um ABZ+PLUS), at aFlow Rate of 3 ml/min, Injection Volume of 5 μl, at room temperature andUV Detection Range at 215 to 330 nm.

Intermediate 1 6-Chloro-N-cyclopropylmethylnicotinamide

6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux inthionyl chloride (2 ml) for 2.5 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in acetone (4 ml),cyclopropylmethylamine (71 mg, 0.10 mmol) and sodium carbonate (500 mg)were added to the solution. The reaction was stirred at room temperaturefor 4 hrs, filtered and the filtrate reduced to dryness under vacuum togive 6-chloro-N-cyclopropylmethylnicotinamide as a cream solid. NMR: δH[²H₆]-DMSO 8.82,(2H, m), 8.23,(1H, dd), 7.63,(1H, d), 3.14,(2H, t),1.01,(1H, m), 0.44,(2H, m), 0.22,(2H, m).

Intermediate 2 6-Chloro-N-(4-methoxyphenyl)nicotinamide

6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux inthionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in DCM (2 ml), p-anisidine (123 mg,0.10 mmol) and sodium carbonate (500 mg) were added to the solution. Thereaction was stirred at room temperature for 4 hrs, filtered and thefiltrate reduced to dryness under vacuum to give6-chloro-N-(4-methoxyphenyl)nicotinamide. NMR: δH [²H₆]-DMSO 10.37,(1H,b), 8.94,(1H, d), 8.34,(1H, dd), 7.70,(1H, d), 7.66,(2H, m), 6.95,(2H,m), 3.75,(3H, s).

Intermediate 3 6-Chloro-N-(3-methoxybenzyl)nicotinamide

6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux inthionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in DCM (2 ml), 3-methoxybenzylamine(137 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to thesolution. The reaction was stirred at room temperature for 4 hrs,filtered and the filtrate reduced to dryness under vacuum to give6-chloro-N-(3-methoxybenzyl)nicotinamide. NMR: δH [²H₆]-DMSO 9.29,(1H,t), 8.88,(1H, d), 8.28,(1H, dd), 7.66,(1H, d), 7.25,(1H, t), 6.90,(2H,m), 6.83,(1H, m), 4.47,(2H, d), 3.74,(3H, s).

Intermediate 4 6-Chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide

6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux inthionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in DCM (2 ml),3-methylsulphonylarninobenzylamine (200 mg, 0.10 mmol) and sodiumcarbonate (500 mg) were added to the solution. The reaction was stirredat room temperature for 4 hrs, filtered and the filtrate reduced todryness under vacuum to give6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide. NMR: δH[²H₆]-DMSO 9.30,(1H, t), 8.88,(1H, d), 8.28,(1H, dd), 7.67,(1H, d),7.23,(1H, t), 7.10,(1H, s), 7.04,91H, d), 6.97,(1H, d), 4.45,(2H, d),2.90,(3H, s).

Intermediate 5 6-Chloro-N-[2-(4-methylpiperazin-1-yl)phenyl]nicotinamide

6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux inthionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in DCM (2 ml),1-(2-aminobenzyl)-4-methylpiperazine (205 mg, 0.10 mmol) and sodiumcarbonate (500 mg) were added to the solution. The reaction was stirredat room temperature for 4 hrs, filtered and the filtrate reduced todryness under vacuum to give6-chloro-N-[2-(4-methylpiperazin-1-yl)phenyl]nicotinamide. NMR: δH[²H₆]-DMSO 11.62,(1H, s), 8.95,(1H, d), 8.32,(1H, dd), 8.25,(1H, d),7.77,(1H, d), 7.34,(1H, m), 7.28,(1H, m), 7.10,(1H, m), 3.73,(2H, s),2.56-2.20,(8H, b), 2.12,(3H, s).

Intermediate 64-Methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

3-Iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide (Intermediate 7) (83mg, 0.20 mmol), bis(pinnacolato)diboron (100 mg, 0.39 mmol), potassiumacetate (97 mg, 1.0 mmol) and PdCl₂dppf (12 mg) were heated at 80° C. inDMF (2.5 ml) for 4 hrs. The cooled reaction was absorbed onto silica,applied to a bond-elut (10 g, silica) and eluted with anethylacetate/cyclohexane gradient (0 to 100%). The solvent wasevaporated from the product fractions under vacuum and the residuetriturated with ether to give4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamideas a white solid (31 mg). LCMS: retention time 3.69 min, MH⁺415.

Intermediate 7 3-Iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide

3-Iodo-4-methylbenzoic acid (154 mg, 0.59 mmol) was heated at 80° C. inthionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in acetone (3 ml),2-(3-aminophenyl)pyridine (100 mg, 0.59 mmol) and sodium carbonate (400mg) were added to the solution. The reaction was stirred at roomtemperature for 11 days, filtered and the filtrate reduced to drynessunder vacuum. The residue was dissolved in ether and filtered through abond-elut (1 g, silica), washing with ether. The solvent was evaporatedfrom the combined filtrate and washings to give3-iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide as a cream foam. NMR:δH CDCl₃ 8.70,(1H, dt), 8.33,(1H, d), 8.18,(1H, t), 7.93-7.89,(2H, m),7.79-7.75,(4H, m), 7.50,(1H, t), 7.35,(1H, d), 7.26,(1H, m), 2.51,(3H,s).

Intermediate 8N-Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

N-Cyclopropyl-3-iodo-4-methylbenzamide (Intermediate 9) (1.1 g, 3.64mmol), bis(pinnacolato)diboron (1.85 g, 7.28 mmol), potassium acetate(1.79 g, 18.2 mmol) and PdCl₂dppf (55 mg) were heated at 85° C. in DMF(30 ml) for 4.5 hrs. The cooled reaction was absorbed onto silica,applied to a bond-elut (10 g, silica) and eluted with anethylacetate/cyclohexane gradient (0 to 100%). The solvent wasevaporated from the product fractions under vacuum and the residuetriturated with cyclohexane to giveN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamideas a white solid (650 mg). NMR: δH [²H₆]-DMSO 8.40,(1H, d), 8.06,(1H,d), 7.76,(1H, dd), 7.23,(1H, d), 2.82,(1H, m), 2.48,(3H, s), 1.30,(12H,s), 0.66,(2H, m), 0.56,(2H, m).

Intermediate 9 N-Cyclopropyl-3-iodo-4-methylbenzamide

3-Iodo-4-methylbenzoic acid (1.0 g, 3.8 mmol) was heated at 80° C. inthionyl chloride (10 ml) for 2 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in DCM (10 ml), cyclopropylamine (0.32ml) and sodium carbonate (2.0 g) were added to the solution. Thereaction was stirred at room temperature for 18 hrs, filtered and thefiltrate reduced to dryness under vacuum. The residue was trituratedwith ether to give N-cyclopropyl-3iodo-4-methylbenzamide as a whitesolid (1.1 g). NMR: δH [²H₆]-DMSO 8.46,(1H, d), 8.24,(1H, d), 7.74,(1H,dd), 7.38,(1H, d), 2.82,(1H, m), 2.38,(3H, s), 0.67,(2H, m), 0.55,(2H,m).

Intermediate 10N-Cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid(Intermediate 17) (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU(3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at roomtemperature for 15 mins. Cyclopropylmethylamine (568 mg, 8.01 mmol) wasadded and the reaction stirred at room temperature for 18 hours. Thesolvent was evaporated under vacuum and the reaction partitioned betweenethyl acetate (250 ml) and water (50 ml). The organic phase was washedwith hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M,50 ml), then dried (magnesium sulphate) and the solvent evaporated undervacuum. The residue was absorbed onto silica and purified by flashcolumn chromatography eluting with cyclohexane/ethyl acetate (4:1). Thesolvent was evaporated from the product fractions under vacuum to giveN-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(1.73 g). LCMS: retention time 3.47 min, MH⁺316. NMR: δH [²H₆]-DMSO8.54,(1H, t), 8.11,(1H, d), 7.82,(1H, dd), 7.26,(1H, d), 3.12,(2H, t),1.32,(12H, s), 1.03,(1H, m), 0.42,(2H, m), 0.22,(2H, m).

Intermediate 114-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide

4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid(2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02mmol) were dissolved in DMF (20 ml) and stirred at room temperature for15 mins. 2-Aminothiazole (801 mg, 8.01 mmol) was added and the reactionstirred at room temperature for 18 hours. The solvent was evaporatedunder vacuum and the reaction partitioned between ethyl acetate (250 ml)and water (50 ml). The organic phase was washed with hydrochloric acid(2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), then dried(magnesium sulphate) and the solvent evaporated under vacuum. Theresidue was absorbed onto silica and purified by flash columnchromatography eluting with cyclohexane/ethyl acetate (4:1). The solventwas evaporated from the product fractions under vacuum to4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide(1.72 g). LCMS: retention time 3.66 min, MH⁺345. NMR: δH [²H₆]-DMSO12.65,(1H, b), 8.32,(1H, d), 8.08,(1H, dd), 7.56,(1H, d), 7.35,(1 h, d),7.28,(1H, d), 2.54,(3H, s), 1.34,(12H, s).

Intermediate 124-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide

4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid(2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02mmol) were dissolved in DMF (20 ml) and stirred at room temperature for15 mins. 2-Aminothiadiazole (810 mg, 8.01 mmol) was added and thereaction stirred at room temperature for 18 hours. The solvent wasevaporated under vacuum and the reaction partitioned between ethylacetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous wasextracted with ethylacetate (2×250 ml). The combined organic extractswere dried (magnesium sulphate) and the solvent evaporated under vacuum.The residue was absorbed onto silica and purified by flash columnchromatography eluting with cyclohexane/ethyl acetate (4:1 then 1:1).The solvent was evaporated from the product fractions under vacuum to4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide(0.95 g). LCMS: retention time 3.34 min, MH⁺346. NMR: δH [²H₆]-DMSO13.08,(1H, b), 9.22,(1H, s), 8.35,(1H, d), 8.11,(1H, dd), 7.38,(1H, d),2.55,(3H, s), 1.34,(12H, s).

Intermediate 13N-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide

N-(3-Iodo-4-methylphenyl)-3-furamide (Intermediate 15) (2.5 g, 7.64mmol), bis(pinnacolato)diboron (2.13 g, 8.41 mmol), potassium acetate(825 mg, 8.41 mmol) and PdCl₂dppf (312 mg, 0.38 mmol) in DMF (20 ml)were heated at 80° C. for 20 hrs. The cooled reaction was absorbed ontosilica and applied to a bond-elut (silica, 10 g) and eluted with acyclohexane/ethyl acetate gradient. The product fractions wereconcentrated under vacuum, dissolved in DMF (40 ml) and reacted withbis(pinnacolato)diboron (7.76 g, 30.57 mmol), potassium acetate (3.0 g,30.57 mmol) and PdCl₂dppf (249 mg, 0.306 mmol) at 80° C. for 23 hrs. Thecooled reaction was absorbed onto silica and applied to bond-eluts(silica, 2×10 g) and eluted with a cyclohexane/ethyl acetate gradient.The product fractions were concentrated under vacuum to giveN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide.LCMS: retention time 3.55 min, MH⁺328. NMR: δH [²H₆]-DMSO 9.86,(1H, b),8.36,(1H, m), 7.86-7.82,(2H, m), 7.77,(1H, t), 7.14,(1H, d), 6.99,(1H,m), 2.41,(3H, s), 1.30,(12H, s).

Intermediate 14N-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide

N-(3-Iodo-4-methylphenyl)thiophene-3-amide (Intermediate 16) (2.64 g,7.64 mmol), bis(pinnacolato)diboron (2.13 g, 8.41 mmol), potassiumacetate (825 mg, 8.41 mmol) and PdCl₂dppf (312 mg, 0.38 mmol) in DMF (20ml) were heated at 80° C. for 20 hrs. The cooled reaction was absorbedonto silica and applied to a bond-elut (silica, 10 g) and eluted with acyclohexane/ethyl acetate gradient. The product fractions wereconcentrated under vacuum, dissolved in DMF (20 ml) and reacted withbis(pinnacolato)diboron (1.77 g, 7.0 mmol), potassium acetate (687 mg,7.0 mmol) and PdCl₂dppf (143 mg, 0.175 mmol) at 80° C. for 16 hrs. Thecooled reaction was absorbed onto silica and applied to a bond-elut(silica, 10 g) and eluted with a cyclohexane/ethyl acetate gradient. Theproduct fractions were concentrated under vacuum to giveN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide.LCMS: retention time 3.65 min, MH⁺344. NMR: δH [²H₆]-DMSO 9.99,(1H, b),8.35,(1H, s), 7.90,(1H, d), 7.85,(1H, dd), 7.63,(2H, m), 7.14,(1H, d),2.42,(3H, s), 1.30,(12H, s).

Intermediate 15 N-(3-Iodo-4-methylphenyl)-3-furamide

3-Furoic acid (2.4 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF(25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml,64.35 mmol) were added and the reaction stirred at room temperature for16 hrs. The solvent was evaporated under vacuum and the residuepartitioned between ethyl acetate (100 ml) and aqueous sodium carbonate(10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N,75 ml), water (75 ml) and brine (75 ml). The organic phase was dried(magnesium sulphate) and absorbed onto silica. The silica was applied toa flash silica column and eluted with cyclohexane/ethyl acetate (3:1).The solvent was evaporated from the product fractions under vacuum togive N-(3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3.52min, MH⁺328. NMR: δH [²H₆]-DMSO 9.92,(1H, b), 8.36,(1H, d), 8.23,(1H,d), 7.80,(1H, t), 7.66,(1H, dd), 7.29,(1H, d), 6.98,(1H, d), 2.33,(3H,s).

Intermediate 16 N-(3-Iodo-4-methylphenyl)thiophene-3-amide

Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT(2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) andDIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at roomtemperature for 16 hrs. The solvent was evaporated under vacuum and theresidue partitioned between ethyl acetate (100 ml) and aqueous sodiumcarbonate (10%, 100 ml). The aqueous layer was extracted with ethylacetate (50 ml) and the combined organic phases washed with hydrochloricacid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase wasdried (magnesium sulphate) and absorbed onto silica. The silica wasapplied to a flash silica column and eluted with cyclohexane/ethylacetate (4:1). The solvent was evaporated from the product fractionsunder vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS:retention time 3.69 min, MH⁺344. NMR: δH [²H₆]-DMSO 10.06,(1H, b),8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd),7.30,(1H, d), 2.34,(3H, s).

Intermediate 174-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid

3-Iodo-4-methylbenzoic acid (10 g, 38.16 mmol), bis(pinnacolato)diboron(14.5 g, 57.24 mmol), potassium acetate (18.73 g, 190.8 mmol) andPdCl₂dppf (3.12 g, 3.8 mmol) in DMF (200ml) were heated at 80° C. for 21hrs. The solvent was evaporated from the cooled reaction under vacuum,the residue dissolved in ethyl acetate (300 ml) and hydrochloric acid(2N, 300 ml) and filtered through celite. The organic phase wasseparated and the aqueous extracted with ethyl acetate (2×300 ml). Thecombined organic extracts were washed with brine (500 ml) and dried(magnesium sulphate). The solvent was evaporated under vacuum and theresidue absorbed onto silica and applied to a silica flash column. Thiswas eluted with cyclohexane/ethyl acetate (5:1). The product fractionswere concentrated under vacuum to give4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid.LCMS: retention time 3.65 min. NMR: δH [²H₆]-DMSO 12.83,(1H, b),8.23,(1H, d), 7.89,(1H, dd), 7.29,(1H, d), 2.51,(3H, s), 1.30,(12H, s).

Intermediate 18N-[4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide

Bis(pinacolato)diborane (7.24 g, 28.5 mmol) was added to a mixture ofN-(3-iodo-4-methylphenyl)-2-pyrrolidin-1-yl-isonicotinamide(Intermediate 19) (7.73 g, 19 mmol) in dimethylformamide (100 ml)potassium acetate (9.32 g, 95 mmol) and PdCl₂dppf and the reaction washeated under an atmosphere of nitrogen at 80° C. for 16 hours. Thereaction was cooled and the solvent removed in vacuo. The residue wastaken up in chloroform (150 ml), washed with water (3×100 ml) and brine(100 ml), dried over magnesium sulfate, filtered and solvent removed invacuo. The residue was purified by column chromatography (20:80 ethylacetate:cyclohexane to 50:50 ethyl acetate:cyclohexane). To giveN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamideas a white solid (1.5 g, 3.7 mmol). LCMS: retention time 2.90 minMH⁺408. NMR: δH—CDCl₃ 8.27 (1H, d), 7.99 (1H, dd), 7.76 (1H, b), 7.65(1H, d), 6.20 (1H, d), 6.82 (1H, b), 6.77 (1H, b), 3.52 (4H, apparentt), 2.52 (3H, s), 2.25 (4H, m).

Intermediate 19N-(3-Iodo-4-methylphenyl)-2-pyrrolidin-1-yl-isonicotinamide

A solution of N-(3-iodo-4-methylphenyl)-2-chloro-isonicotinamide(Intermediate 20) (7.00 g, 18.8 mmol) in pyrrolidine (20 ml) was heatedat 80° C. under an atmosphere of nitrogen for 16 hours. Excesspyrrolidine was removed in vacuo and the residue was titurated withdietheyl ether (20 ml). The resulting solid was collected by filtrationand dried in vacuo to giveN-(3-iodo-4-methylphenyl)-2-pyrrolidin-1-yl-isonicotinamide as a paleyellow solid (7.73 g, 18 mmol). LCMS: retention time 2.77 min MH⁺408.NMR: δH [²H₆]-DMSO 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H,dd), 7.72 (1H, dd), 6.97 (1H, brd), 6.88 (1H, b), 3.45 (2H, apparent t),3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).

Intermediate 20 2-Chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide

2-Chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol),diisopropylethyl amine (10.9 ml, 63 mmol) and 4-iodo-3-methylaniline(5.00 g, 21 mmol) in dimethylformamide (50 ml) were heated undernitrogen for 16 hours. The reaction was cooled, solvent removed in vacuoand the residue taken up in dichloromethane (150 ml). The organicsolution was washed with water (3×100 ml) and brine (100 ml), dried overmagnesium sulfate, filtered and solvent removed in vacuo. The residuewas purified by column chromatography (40:60 ethyl acetate:cyclohexane)to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a whitesolid (7.00 g, 18.8 mmol). LCMS: retention time 3.59 min MH⁺373. NMR: δH[²H₆]-DMSO 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87(1H, dd), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s).

Intermediate 21 6-Chloro-N-cyclopropylmethylnicotinamide

6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux inthionyl chloride (2 ml) for 2.5 hrs. The reaction was allowed to cool toroom temperature and the excess thionyl chloride evaporated undervacuum. The residue was dissolved in acetone (4 ml),cyclopropylmethylamine (71 mg, 0.10 mmol) and sodium carbonate (500 mg)were added to the solution. The reaction was stirred at room temperaturefor 4 hrs, filtered and the filtrate reduced to dryness under vacuum togive 6-chloro-N-cyclopropylmethylnicotinamide as a cream solid. NMR: δH[²H₆]-DMSO 8.82,(2H, m), 8.23,(1H, dd), 7.63,(1H, d), 3.14,(2H, t),1.01,(1H, m), 0.44,(2H, m), 0.22,(2H, 10 m).

General Method A

6-Bromonicotinic acid (100 mg, 0.5 mmol) was heated at 95° C. in thionylchloride (0.63 ml) for 2 hours. The excess thionyl chloride wasevaporated under vacuum and the residue dissolved in DCM (2 ml). To thissolution, amine (0.5 mmol) and sodium carbonate (100 mg) were added andthe reaction was stirred at room temperature for 2 hours. The reactionwas filtered and the residue washed with DCM. The combined filtrate andwashings were reduced to dryness to give the desired6-chloronicotinamide. Retention time Compound Amine MH⁺ (minutes)Intermediate 22: 6-Chloro-N-(3- 3-methylbutylamine 227 2.92methylbutyl)nicotinamide Intermediate 23: 6-Chloro-N-(1-1-cyclopropylethylamine 225 2.65 cyclopropylethyl)nicotinamideIntermediate 24: 6-Chloro-N-(2,2- 2,2-dimethylpropylamine 227 2.82dimethylpropyl))nicotinamide Intermediate 25: 6-Chloro-N-(2,2- 2,2- 2252.67 dimethylcyclopropyl)nicotinamide dimethylcyclopropylamineIntermediate 26: 6-Chloro-N- cyclopropylamine 197 2.19cyclopropylnicotinamide Intermediate 27: 6-Chloro-N-cyclohexylmethylamine 253 3.18 cyclohexylmethylnicotinamide Intermediate28: 6-Chloro-N- cyclobutylamine 211 2.51 cyclobutylnicotinamideIntermediate 29: 6-Chloro-N-(2- 2-methylpropylamine 213 2.63methylpropyl)nicotinamide Intermediate 30: 6-Chloro-N- propylamine 1992.38 propylnicotinamide Intermediate 31: 6-Chloro-N- cyclopentylamine225 2.70 cyclopentylnicotinamide

Intermediate 32 6-Chloro-N-cyclobutylmethylnicotinamide

6-Chloro-N-cyclobutylmethylnicotinamide was prepared fromcyclobutylmethylamine using General Method A.

NMR: δH [²H₆]-DMSO 8.81,(1H, d), 8.70,(1H, bt), 8.22,(1H, dd), 7.64,(1H,d), 3.30,(2H, t), 2.52,(1H, m), 1.99,(2H, m), 1.81,(2H, m), 1.73,(2H,m).

Intermediate 33 6-Chloro-N-(1-methylpropyl)nicotinamide

6-Chloro-N-(1-methylpropyl)nicotinamide was prepared from1-methylpropylamine using General Method A.

NMR: δH [²H₆]-DMSO 8.82,(1H, d), 8.42,(1H, d), 8.24,(1H, dd), 7.64,(1H,d), 3.91,(1H, m), 1.51,(2H, m), 1.15,(3H, d), 0.87,(3H, t).

Intermediate 34N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (Intermediate 35, 900mg), bispinnacolatodiboron (4.5 g), potassium acetate (2.1 g) andPdCl₂dppf (75 mg) were mixed in DMF (40 ml) and heated at 100° C. for 18hours. The cooled reaction was absorbed onto silica and applied to SPE's(Si 2×10 g). The SPE's were eluted with an ethylacetate/cyclohexanegradient (0-6.25% ethylacetate). The solvent was evaporated from theproduct fractions under vacuum and the residue recrystallised fromcyclohexane to giveN-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(260 mg).

LCMS: MH⁺320, retention time 3.39 mins.

Intermediate 35 3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide

3-Fluoro-4-methylbenzoic acid (462 mg, 3.0 mmol) was added to a stirredmixture of bromine (2.31 ml, 45 mmol) and iron powder (252 mg, 4.5 mmol)under nitrogen. The reaction was stirred at 20° C. for 4 hours and thenleft to stand for 16 hours. Sodium thiosulphate solution (200 ml) wasadded and the product was extracted into ethyl acetate (3×150 ml). Ethylacetate extracts were combined and evaporated in vacuo. The crudeproduct (mixture of isomers) was dissolved in dimethylformamide (7 ml).Cyclopropylamine (208 μl, 3.0 mmol), HOBT (405 mg, 3.0 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (575 mg, 3.0mmol) and DIPEA (525 μl, 3.0 mmol) were added to the stirred solution.The reaction was stirred for 5 hours at 20° C. Solvent was removed invacuo and the residue was partitioned between ethyl acetate and water.Combined ethyl acetate extracts were washed sequentially with aqueoussodium hydrogen carbonate and hydrochloric acid (0.5M), then dried(magnesium sulphate). The ethyl acetate was evaporated in vacuo and theresidue was purified by silica biotage chromatography eluting withcyclohexane:ethyl acetate (6:1) to give3-bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (359 mg, 44%).

NMR: δH-CDCl₃ 7.68,(1H, s), 7.39,(1H, d), 6.19,(1H, bs), 2.88,(1H, m),2.36,(3H, d), 0.88,(2H, m), 0.63,(2H, m). LCMS: MH⁺272.

Intermediate 36{5-[(Cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid

N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5 g)in THF (75 ml) was cooled to 0° C. and sodium hydride (60%, 1.23 g)added portionwise over 10 minutes. Once effervescence had ceased thereaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20ml) added over 25 minutes maintaining a temperature of <−70° C.Triisopropyl borate (8 ml) was added to the reaction over 10 minutes andthe reaction stirred at −70° C. for 4hours. The reaction was quenchedwith water (20 ml) and the mixture allowed to warm to 5° C. The reactionwas concentrated under vacuum and the residue partitioned betweensaturated ammonium chloride and ethyl acetate. The organic phase waswashed with saturated ammonium chloride, brine, dried (sodium sulphate)and reduced to dryness under vacuum. The residue was dissolved inDCM/ethyl acetate and purified by column chromatography on silicaeluting with an ethyl acetate/DCM gradient (5-100% ethyl acetate) andthen methanol. The product fractions were combined and the solventevaporated under vacuum to give{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid.LCMS MH⁺238, retention time 2.19 min.

Intermediate 37 N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide

N-Iodosuccinimide (22.5 g) was added in portions to a solution of3-fluoro-4-methylbenzoic acid (15.4 g) in trifluoromethanesulphonic acid(100 ml) at 0° C. over 3 hours and the reaction then allowed to warm toroom temperature overnight. The reaction mixture was poured intoice/water (400 ml) and the precipitate filtered off and washed withwater. The solid remaining was dissolved in ethyl acetate, washed withaqueous sodium thiosulphate (x2), then brine, dried (magnesium sulphate)and the solvent evaporated under vacuum. The residue was mixed withthionyl chloride (30 ml) and heated at 100° C. for 2.5 hours. The excessthionyl chloride was removed from the cooled reaction under vacuum andthe residue dissolved in DCM (100 ml). Sodium carbonate (25 g ) andcyclopropylamine (1 3 ml) were added to the solution and the reactionstirred at room temperature for 72 hours. The reaction was filtered andthe residue washed with DCM and ethyl acetate. The solvent wasevaporated from the combined filtrate and washings under vacuum. Theresidue was absorbed onto silica and chromatographed on a flash silicacolumn eluting with an ethyl acetate/cyclohexane gradient (22-28% ethylacetate). Appropriate fractions were reduced to dryness under vacuum togive N-cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide. LCMS; MH+320,retention time 3.16 minutes.

Intermediate 386-{5-[(Cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid

N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(3.2 g), methyl 6-chloronicotinate (1.73 g),tetrakis(triphenylphosphine)palladium (210 mg) and aqueous sodiumhydrogen carbonate (1M, 30 ml) were mixed in propan-2-ol (100 ml) andheated at 90° C. for 18 hours. The reaction was allowed to cool and thepropan-2-ol removed under vacuum. The residue was partitioned betweenethyl acetate and aqueous sodiumhydrogen carbonate (1M). The aqueousphase was acidified with hydrochloric acid (2N) and extracted with ethylacetate (x2). The organic extracts were washed with brine, dried(magnesium sulphate) and reduced to dryness under vacuum. The resultingfoam was triturated with ether to give6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acidas a solid.

LCMS: MH⁺315, retention time 2.87 mins.

Intermediate 39 (2-Ethylcyclopropyl)methylamine

A solution of 2-ethylcyclopropylcarboxamide (250 mg, 2.2 mmol) in THFwas heated to reflux. Borane-dimethylsulphide (1M solution in DCM, 3.2ml, 3.2 mmol) was added dropwise over 30 minutes and the reactionrefluxed for 16 hours. Hydrochloric acid (6N, 0.5 ml) was added dropwiseand the mixture heated at reflux for 30 minutes. The cooled reactionmixture was diluted with water (20 ml), washed with ether (50 ml) andbasified with sodium hydroxide (6N). The aqueous was extracted withether (50 ml×3) and ethyl acetate (50 ml). The combined organic extractswere dried (magnesium sulphate), acidified with hydrogen chloride (3.3Min methanol) and reduced to dryness under vacuum to give(2-ethylcyclopropyl)methylamine (230 mg). NMR: δH [²H₆]-DMSO 7.85,(3H,b), 2.66,(2H, d), 1.30-1.13,(2H, m), 0.91,(3H, t), 0.77-0.66,(2H, m),0.46,(1H, m), 0.33,(1H, m).

General Method B

The 2-chloropyridine (0.05 mmol), phenyl pinnacolborane (0.05 mmol),tetrakis(triphenylphosphine) palladium (1 mg) and aqueous sodiumcarbonate (0.25 ml) in propan-2-ol (1 ml) were heated at 85° C. undernitrogen for 18 hours. The cooled reaction was diluted with ethylacetate (4 ml) and methanol (2 ml) and filtered through an SCX bond-elut(1 g). The product was eluted with 10% ammonia (s.g. 0.88) in methanol.The solvents were evaporated and the residue triturated with ether.

Example 1N-(3-[5-(Cyclopropylmethyl-carbamoyl)-pyridin-2-yl]-4-methyl-phenyl)-2-pyrrolidin-1-yl-isonicotinamide

6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25 mg, 0.098mmol) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide(Intermediate 18) (30 mg, 0.074 mmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 80°C. in DMF (1 ml) for 18 hours. The reaction was absorbed onto silica,applied to a bond-elut (10 g, silica) and eluted with anethylacetate/cyclohexane (0 to 100%), then acetone and methanol. Thesolvent was evaporated from the product fractions under vacuum and theresidue triturated with ether to giveN-(3-[5-(cyclopropylmethyl-carbamoyl)-pyridin-2-yl]-4-methyl-phenyl)-2-pyrrolidin-1-yl-isonicotinamideas a white solid (20 mg). LCMS: retention time 2.42 min, MH⁺456. NMR: δH[²H₆]-DMSO 10.32,(1H, s), 9.09,(1H, s), 8.82,(1H, t), 8.28,(1H, m),8.19,(1H, m), 7.85,(1H, t), 7.76,(1H, m), 7.64,(1H, m), 7.31,(1H, m),6.98,(1H, m), 6.88,(1H, s), 3.43,(4H, m), 3.18,(2H, in), 2.31,(3H, s),1.95,(4H, m), 1.07,(1H, m), 0.45,(2H, m), 0.25,(2H, m).

Example 2N-Cyclopropylmethyl-6-[2-methyl-5-(3-pyridin-2-yl-phenylcarbamoyl)-phenyl]-nicotinamide

6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5 mg,0.073 mmol) and4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 6) (30 mg, 0.072 mmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90°C. in DMF (1 ml) for 4 hours. The reaction was absorbed onto silica,applied to a bond-elut (5 g, silica) and eluted with anethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent wasevaporated from the product fractions under vacuum and the residuetriturated with ether to giveN-cyclopropylmethyl-6-[2-methyl-5-(3-pyridin-2-yl-phenylcarbamoyl)-phenyl]-nicotinamideas a white solid (20 mg). LCMS: retention time 3.18 min, MH⁺463. NMR: δH[²H₆]-DMSO 10.43,(1H, s), 9.14,(1H, s), 8.86,(1H, t), 8.69,(1H, s),8.53,(1H, s), 8.34,(1H, d), 8.11,(1H, s), 8.01,(1H, d), 7.95-7.89,(3H,m), 7.81-7.78,(2H, m), 7.53-7.46,(2H, m), 7.38,(1H, t), 3.21,(2H, t),2.44,(3H, s), 1.07,(1H, m), 0.47,(2H, m), 0.27,(2H, m).

Example 36-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide

6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5 mg, 0.10mmol) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 8) (30 mg, 0.10 mmol), aqueous sodium carbonate (2N, 0.5ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90°C. in DMF (1 ml) for 3 hours. The reaction was absorbed onto silica,applied to a bond-elut (5 g, silica) and eluted with anethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent wasevaporated from the product fractions under vacuum and the residuetriturated with ether to6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamideas a cream solid. LCMS: retention time 2.70 min, MH⁺350. NMR: δH[²H₆]-DMSO 9.11,(1H, s), 8.84,(1H, t), 8.48,(1H, d), 8.31,(1H, dd),7.88,(1H, s), 7.81,(1H, d), 7.70,(1H, d), 7.41,(1H, d), 3.20,(1H, t),2.86,(1H, m), 2.37,(3H, s), 1.06,(1H, m), 0.69,(2H, m), 0.57,(2H, m),0.46,(2H, m), 0.26,(2H, m).

Example 4N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide

N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamidewas prepared from 6-chloro-N-cyclopropylmethylnicotinamide(Intermediate 1) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide(Intermediate 12) using General Method B. LCMS: retention time 2.79 min,MH⁺394. NMR: δH [²H₆]-DMSO 13.14,(1H, b), 9.24,(1H, s), 9.14,(1H, s),8.86,(1H, t), 8.35,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.82,(1H, d),7.54,(1H, d), 3.21,(2H, t), 2.46,(3H, s), 1.07,(1H, m), 0.47,(2H, m),0.27,(2H, m).

Example 5N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide

N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamidewas prepared from 6-chloro-N-cyclopropylmethylnicotinamide(Intermediate 1) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide(Intermediate 11) using General Method B. LCMS: retention time 2.99 min,MH⁺393. NMR: δH [²H₆]-DMSO 12.71,(1H, b), 9.13,(1H, s), 8.86,(1H, t),8.34,(1H, d), 8.21,(1H, s), 8.07,(1H, d), 7.81,(l1H, d), 7.57,(1H, d),7.52,(1H, d), 7.29,(1H, d), 3.21,(2H, t), 2.45,(3H, s), 1.07,(1H, m),0.47,(2H, m), 0.27,(2H, m).

Example 66-[5-(Cyclopropylmethylcarbamoyl)-2-methyl-phenyl]-N-cyclopropylmethyl-nicotinamide

6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl-nicotinamidewas prepared from 6-chloro-N-cyclopropylmethylnicotinamide(Intermediate 1) andN-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 10) using General Method B. LCMS: retention time 2.87 min,MH⁺364. NMR: δH [²H₆]-DMSO 9.10,(1H, s), 8.83,(1H, t), 8.60,(1H, t),8.30,(1H, dd), 7.92,(1H, s), 7.84,(1H, d), 7.71,(1H, d), 7.41,(1H, d),3.19,(2H, t), 3.13,(2H, t), 2.37,(3H, s), 1.03,(2H, m), 0.44,(4H, m),0.23,(4H, m).

Example 7N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide

N-Cyclopropylmethyl-6-[5-(fur-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamidewas prepared from 6-chloro-N-cyclopropylmethylnicotinamide(Intermediate 1) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide(Intermediate 13) using General Method B. LCMS: retention time 2.96 min,MH⁺376. NMR: δH [²H₆]-DMSO 9.99,(1H, s), 9.10,(1H, s), 8.83,(1H, t),8.38,(1H, s), 8.30,(1H, d), 7.80,(2H, s), 7.75,(1H, d), 7.66,(1H, d),7.30,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(2H, m),0.27,(2H, m).

Example 8N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]-nicotinamide

N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]-nicotinamidewas prepared from 6-chloro-N-cyclopropylmethylnicotinamide(Intermediate 1) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide(Intermediate 14) using General Method B. LCMS: retention time 3.07 min,MH⁺392. NMR: δH [²H₆]-DMSO 10.11,(1H, s), 9.11,(1H, s), 8.83,(1H, t),8.35,(1H, s), 8.30,(1H, dd), 7.85,(1H, s), 7.78,(1H, d), 7.67-7.63,(3H,m), 7.31,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(1H,m), 0.27,(1H, m).

Example 96-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(4-methoxyphenyl)-nicotinamide

6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamidewas prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate2) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 8) using General Method B. LCMS: retention time 2.96 min,MH⁺402. NMR: δH [²H₆]-DMSO 10.38,(1H, s), 9.20,(1H, s), 8.49,(1H, d),8.40,(1H, dd), 7.91,(1H, s), 7.82,(1H, d), 7.76,(1H, d), 7.71,(2H, d),7.43,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 2.87,(1H, m), 2.40,(3H, s),0.70,(2H, m), 0.58,(2H, m).

Example 10N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate2) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide(Intermediate 12) using General Method B. LCMS: retention time 3.05 min,MH⁺446. NMR: δH [²H₆]-DMSO 13.15,(1H, b), 10.41,(1H, s), 9.24,(2H, m),8.45,(1H, dd), 8.28,(1H, s), 8.11,(1H, d), 7.88,(1H, d), 7.71,(2H, d),7.56,(1H, d), 6.97,(2H, d), 3.76,(3H, s), 2.48,(3H, s).

Example 11N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate2) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide(Intermediate 11) using General Method B. LCMS: retention time 3.22 min,MH⁺445. NMR: δH [²H₆]-DMSO 12.72,(1H, s), 10.40,(1H, s), 9.22,(1H, d),8.44,(1H, dd), 8.24,(1H, s), 8.09,(1H, d), 7.87,(1H, d), 7.71,(2H, d),7.58,(1H, d), 7.53,(1H, d), 7.30,(1H, d), 6.97,(2H, d), 3.76,(3H, s),2.48,(3H, s).

Example 126-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(4-methoxyphenyl)-nicotinamide

6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamidewas prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate2) andN-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 10) using General Method B. LCMS: retention time 3.12 min,MH⁺416. NMR: δH [²H₆]-DMSO 10.39,(1H, s), 9.21,(1H, d), 8.63,(1H, t),8.41,(1H, dd), 7.96,(1H, s), 7.86,(1H, d), 7.79,(1H, d), 7.71,(2H, d),7.44,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 3.15,(2H, t), 2.41,(3H, s),1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).

Example 136-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide

6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamidewas prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate2) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide(Intermediate 13) using General Method B. LCMS: retention time 3.19 min,MH+428. NMR: δH [²H₆]-DMSO 10.38,(1H, s), 10.00,(1H, s), 9.19,(1H, s),8.38,(2H, m), 7.83,(1H, s), 7.80,(1H, s), 7.76,(1H, s), 7.73-7.69,(3H,m), 7.32,(1H, s), 7.01,(1H, s), 6.96,(2H, d), 3.76,(3H, s), 2.34,(3H,s).

Example 146-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methoxybenzyl)-nicotinamide

6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamidewas prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate3) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 8) using General Method B. LCMS: retention time 2.94 min,MH⁺416. NMR: δH [²H₆]-DMSO 9.29,(1H, t), 9.15,(1H, s), 8.48,(1H, d),8.35,(1H, d), 7.89,(1H, s), 7.81,(1H, d), 7.72,(1H, d), 7.41,(1H, d),7.26,(1H, t), 6.93,(2H, m), 6.84,(1H, s), 4.51,(2H, d), 3.75,(3H, s),2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).

Example 15N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate3) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide(Intermediate 12) using General Method B. LCMS: retention time 3.02 min,MH⁺460. NMR: δH [²H₆]-DMSO 13.14,(1H, b), 9.32,(1H, t), 9.24,(1H, s),9.18,(1H, d), 8.40,(1H, dd), 8.26,(1H, s), 8.10,(1H, d), 7.84,(1H, d),7.55,(1H, d), 7.27,(1H, t), 6.94,(2H, m), 6.84,(1H, d), 4.53,(2H, d),3.75,(3H, s), 2.46,(3H, s).

Example 16N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate3) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide(Intermediate 11) using General Method B. LCMS: retention time 3.20 min,MH⁺459. NMR: δH [²H₆]-DMSO 12.71,(1H, b), 9.31,(1H, t), 9.17,(1H, d),8.39,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.83,(1H, d), 7.57,(1H, d),7.52,(1H, d), 7.29-7.25,(2H, m), 6.94,(2H, m), 6.84,(1H, d), 4.52,(2H,d), 3.75,(3H, s), 2.45,(3H, s).

Example 176-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methoxybenzyl)-nicotinamide

6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) andN-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 10) using General Method B. LCMS: retention time 3.07 min,MH⁺430. NMR: δH [²H₆]-DMSO 9.30,(1H, t), 9.16,(1H, d), 8.62,(1H, t),8.36,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.74,(1H, d), 7.43,(1H, d),7.27,(1H, t), 6.94-6.92,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H,s), 3.14,(2H, t), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H,m).

Example 186-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide

6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamidewas prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate3) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide(Intermediate 13) using General Method B. LCMS: retention time 3.17 min,MH⁺442. NMR: δH [²H₆]-DMSO 9.99,(1H, s), 9.29,(1H, t), 9.15,(1H, d),8.38,(1H, s), 8.34,(1H, dd), 7.81,(2H, m), 7.75,(1H, d), 7.67,(1H, d),7.31-7.25 (2H, m), 7.00.(1H, s), 6.94,(2H, m), 6.84,(1H, d), 4.51,(2H,d), 3.75,(3H, s), 2.32,(3H, s).

Example 19N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide

N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamidewas prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate3) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide(Intermediate 14) using General Method B. LCMS: retention time 3.27 min,MH⁺458. NMR: δH [²H₆]-DMSO 10.12,(1H, s), 9.29,(1H, t), 9.15,(1H, d),8.35-8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d), 7.68-7.65,(3H, s),7.32-7.24,(2H, m), 6.94,(2H, m), 6.84,(2H, d), 4.51,(2H, d), 3.75,(3H,s), 2.32,(3H, s).

Example 206-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide

6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamidewas prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide(Intermediate 4) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 8) using General Method B. LCMS: retention time 2.71 min,MH⁺479. NMR: δH [²H₆]-DMSO 9.33,(1H, t), 9.15,(1H, s), 8.48-8.33,(3H,m), 7.89,(1H, s), 7.81,(1H, d), 7.73,(1H d), 7.41,(1H, d), 7.31,(1H, t),7.21,(1H, s), 7.10,(2H, m), 4.51,(2H, d), 2.99,(3H, s), 2.86,(1H, m),2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).

Example 21N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide(Intermediate 4) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide(Intermediate 12) using General Method B. LCMS: retention time 2.80 min,MH⁺523. NMR: δH [²H₆]-DMSO 9.35,(1H, t), 9.17,(2H, m), 8.38,(1H, d),8.26,(1H, s), 8.09,(1H, d), 7.83,(1H, d), 7.52,(1H, d), 7.31,(1H, t),7.22,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 2.99,(3H, s), 2.46,(3H, s).

Example 22N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide(Intermediate 4) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide(Intermediate 11) using General Method B. LCMS: retention time 2.96 min,MH⁺522. NMR: δH [2H6]-DMSO 10.19,(2H, b), 9.35,(1H, t), 9.17,(1H, s),8.38,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.84,(1H, d), 7.57,(1H, d),7.52,(1H, d), 7.31-7.28,(2H, m), 7.22,(1H, s), 7.11,(2H, m), 4.52,(2H,d), 2.99,(3H, s), 2.45,(3H, s).

Example 236-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide

6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4)andN-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 10) using General Method B. LCMS: retention time 2.88 min,MH⁺493. NMR: δH [²H₆]-DMSO 9.34,(1H, t), 9.16,(1H, d), 8.96,(1H, b),8.62,(1H, t), 8.35,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.75,(1H, d),7.43,(1H, d), 7.31,(1H, t), 7.21,(1H, s), 7.11,(2H, m), 4.52,(2H, d),3.14,(2H, t), 2.99,(3H, s), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m),0.23,(2H, m).

Example 246-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methylsulphonylaminobenzyl)-nicotinamide

6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4)andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide(Intermediate 13) using General Method B. LCMS: retention time 2.93 min,MH⁺505. NMR: δH [²H₆]-DMSO 9.99,(1H, s), 9.32,(1H, t), 9.15,(1H, d),8.95,(1H, b), 8.38,(1H, s), 8.33,(1H, dd), 7.81,(2H, d), 7.75,(1H, d),7.68,(1H, d), 7.33-7.30,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 7.01,(1H,s), 4.51,(2H, d), 2.99,(3H, s), 2.32,(3H, s).

Example 25N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide

N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamidewas prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide(Intermediate 4) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide(Intermediate 14) using General Method B. LCMS: retention time 3.03 min,MH⁺521. NMR: δH [²H₆]-DMSO 10.12,(1H, s), 9.33,(1H, t), 9.15,(1H, s),8.78,(1H, b), 8.36-8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d),7.69-7.65,(3H, in), 7.31,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 4.51,(2H,d), 2.99,(3H, s), 2.32,(3H, s).

Example 266-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide

6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamidewas prepared from6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide(Intermediate 5) andN-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 8) using General Method B. LCMS: retention time 2.36 min,MH⁺484. NMR: δH [²H₆]-DMSO 11.70,(1H, b), 9.23,(1H, s), 8.50,(1H, d),8.38,(1H, d), 8.33,(1H, d), 7.92,(1H, s), 7.83,(2H, m), 7.43,(1H, d),7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 2.87,(1H, m),2.67-2.24,(11H, m), 2.13,(3H, s), 0.70,(2H, m), 0.58,(2H, m).

Example 27N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide(Intermediate 5) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide(Intermediate 12) using General Method B. LCMS: retention time 2.43 min,MH⁺528. NMR: δH [²H₆]-DMSO 13.07,(1H, b), 11.74,(1H, s), 9.26,(1H, s),9.21,(1H, s), 8.43,(1H, d), 8.34,(1H, d), 8.29,(1H, s), 8.12,(1H, d),7.93,(1H, d), 7.56,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t),3.78,(2H, s), 2.67-2.26,(11H, m), 2.11,(3H, s).

Example 28N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide

N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamidewas prepared from6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide(Intermediate 5) and4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide(Intermediate 11) using General Method B. LCMS: retention time 2.53 min,MH⁺527. NMR: δH [²H₆]-DMSO 12.73,(1H, b), 11.70,(1H, b), 9.26,(1H, d),8.43,(1H, dd), 8.33,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.93,(1H, d),7.58,(1H, d), 7.54,(1H, d), 7.36,(1H, t), 7.30,(2H, m), 7.12,(1H, t),3.78,(2H, s), 2.67-2.25,(11H, b), 2.14,(3H, s).

Example 296-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide

6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamidewas prepared from6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide(Intermediate 5) andN-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 10) using General Method B. LCMS: retention time 2.46 min,MH⁺498. NMR: δH [²H₆]-DMSO 11.67,(1H, b), 9.24,(1H, s), 8.63,(1H, t),8.39,(1H, d), 8.32,(1H, d), 7.97,(1H, s), 7.88-7.83,(2H, m), 7.45,(1H,d), 7.36,(1H, t), 7.30,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 3.15,(2H,t), 2.70-2.21,(11H, m), 1.04,(1H, m), 0.43,(2H, m), 0.23,(2H, m).

Example 30 6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide

6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamidewas prepared from6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide(Intermediate 5) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide(Intermediate 13) using General Method B. LCMS: retention time 2.53 min,MH⁺510. NMR: δH [²H₆]-DMSO 11.64,(1H, b), 10.02,(1H, s), 9.23,(1H, s),8.38,(2H, m), 8.31,(1H, d), 7.86,(1H, s), 7.80,(1H, s), 7.76,(2H, m),7.38-7.29,(3H, m), 7.11,(1H, t), 7.01,(1H, s), 3.77,(2H, s),2.66-2.20,(11H, m), 2.16,(3H, s).

Example 31N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide

N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamidewas prepared from6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide(Intermediate 5) andN-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide(Intermediate 14) using General Method B. LCMS: retention time 2.58 min,MH⁺526. NMR: δH [²H₆]-DMSO 11.64,(1H, b), 10.14,(1H, s), 9.23,(1H, s),8.38,(2H, m), 8.31,(1H, d), 7.91,(1H, s), 7.79-7.75,(2H, in), 7.65,(2H,in), 7.38-7.29,(3H, m), 7.11,(1H, t), 3.77,(2H, s), 2.67-2.24,(11H, in),2.16,(3H, m).

General Method C

The 6-chloronicotinamide (25 mg),N-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(Intermediate 34, 15 mg), tetrakis(triphenylphosphino)palladium (2 mg)and aqueous sodium hydrogen carbonate (1M, 0.5 ml) were mixed inpropan-2-ol (2 ml) and heated at reflux for 18 hours. The propan-2-olwas evaporated and the residue diluted with ethylacetate/cyclohexane(1:2). The solution was applied to a SPE (Si, 2 g) and eluted withethylacetate/cyclohexane (1:2) and then ethylacetate. The solvent wasevaporated from the ethylacetate fraction and the residue trituratedwith ether to give the desired product as a white solid.

Examples 32 to 44 may also be prepared using{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid(Intermediate 36) in place of Intermediate 34. Retention 6- timeCompound Structure Chloronicotinamide MH⁺ (minutes) Example 32 6-(5-Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N- cyclopropylmethyl-nicotinamide

6-Chloro-N- cyclopropylmethyl- nicotinamide (Intermediate 21) 368 2.78Example 33 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-(3-methylbutyl)- nicotinamide

6-Chloro-N-(3- methylbutyl)nicotinamide (Intermediate 22) 384 3.10Example 34 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-cyclopropylmethyl- nicotinamide

6-Chloro-N- cyclopropylmethyl- nicotinamide (Intermediate 32) 382 3.01Example 35 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-(1-cyclopropylethyl)- nicotinamide

6-Chloro-N-(1- cyclopropylethyl) nicotinamide (Intermediate 23) 382 2.95Example 36 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)- nicotinamide

6-Chloro-N-(2,2- dimethylpropyl)) nicotinamide (Intermediate 24) 3843.01 Example 37 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylcyclopropyl)- nicotinamide

6-Chloro-N-(2,2- dimethylcyclopropyl) nicotinamide (Intermediate 25) 3822.90 Example 38 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl-phenyl)-N- cyclopropyl- nicotinamide

6-Chloro-N- cyclopropylnicotinamide (Intermediate 26) 354 2.60 Example39 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-cyclohexylmethyl- nicotinamide

6-Chloro-N- cyclohexylmethyl- nicotinamide (Intermediate 27) 410 3.22Example 40 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl-phenyl)-N-cyclobutyl- nicotinamide

6-Chloro-N- cyclobutylnicotinamide (Intermediate 28) 368 2.79 Example 416-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-(2-methylpropyl)- nicotinamide

6-Chloro-N-(2- methylpropyl) nicotinamide (Intermediate 29) 370 2.86Example 42 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-(1-methylpropyl)- nicotinamide

6-Chloro-N-(1- methylpropyl) nicotinamide (Intermediate 33) 370 2.84Example 43 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl-phenyl)-N-propyl- nicotinamide

6-Chloro-N- propylnicotinamide (Intermediate 30) 356 2.72 Example 446-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N- cyclopentyl-nicotinamide

6-Chloro-N- cyclopentylnicotinamide (Intermediate 31) 382 2.92General Method D

Intermediate 38 (40 μmol) in DMF(0.5 ml) was treated with HATU (1.12 eq)and DIPEA (3 eq). On shaking a solution was formed which was added to asolution of amine (1.2-2.0 eq) in DMF (0.5 ml). After shaking thereactions were left overnight at room temperature. The solvent wasremoved in vacuo, the residue dissolved in chloroform (1.0 ml) andapplied to an SPE (NH_(2,) 0.5 g). The product was eluted withchloroform (1.5 ml), ethyl acetate (1.5 ml) and methanol/ethyl acetate(1:9, 1.5 ml). The solvent was evaporated under vacuum from the productfraction. Retention time Compound Amine MH⁺ (minutes) Example 452-aminomethylthiazole 411 2.79 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(1,3- thiazol-2- ylmethyl)nicotinamideExample 46 2-(2-aminoethyl)thiazole 425 2.78 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[2-(1,3-thiazol-2- yl)ethyl]nicotinamide Example 47 2-methylbenzylamine 418 3.266-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2-methylbenzyl)nicotinamide Example 48 2,4,5-trifluorobenzylamine 458 3.296-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2,4,5-trifluorobenzyl)nicotinamide Example 49 2,5-difluorobenzylamine 440 3.216-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2,5-difluorobenzyl)nicotinamide Example 50 3,4-difluorobenzylamine 440 3.246-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3,4-difluorobenzyl)nicotinamide Example 51 3-chlorobenzylamine 438 3.33N-(3-chlorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamide Example 52 4-chlorobenzylamine 438 3.34N-(4-chlorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamide Example 53 3-chloro-2-fluorobenzylamine 4563.36 N-(3-chloro-2- fluorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}nicotinamide Example 545-fluoro-2-methylbenzylamine 436 3.30 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(5-fluoro- 2-methylbenzyl)nicotinamide Example 55 2-chloro-3,6-difluorobenzylamine474 3.31 N-(2-chloro-3,6- difluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}nicotinamideExample 56 2-pentylamine 384 3.14 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(1- methylbutyl)nicotinamide Example 572,3-difluoro-4-methylbenzylamine 454 3.36 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2,3-difluoro-4- methylbenzyl)nicotinamide Example 582,3,6-trifluorobenzylamine 458 3.29 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(2,3,5- trifluorobenzyl)nicotinamide Example59 1,3-dimethylbutylamine 398 3.28 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(1,3- dimethylbutyl)nicotinamide Example 603-fluoro-4-methylbenzylamine 436 3.32 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3-fluoro- 4-methylbenzyl)nicotinamide Example 61 5-chloro-2-fluorobenzylamine 4563.36 N-(5-chloro-2- fluorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}nicotinamide Example 62 2-phenylethylamine 4183.20 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2-phenylethyl)nicotinamide Example 63 2-methoxy-2-methylpropylamine 4002.79 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2-methoxy-2- methylpropyl)nicotinamide Example 64 2-methoxyethylamine 3722.63 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2-methoxyethyl)nicotinamide Example 65 3,3-dimethylbutylamine 398 3.306-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3,3-dimethylbutyl)nicotinamide Example 66 2-t-butoxyethylamine 414 2.98N-(2-tert-butoxyethyl)-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamide Example 67 1,1-dimethylpropylamine 384 3.176-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(tert-pentyl)nicotinamide Example 68 2-(aminomethyl)-4-methylthiazole 425 2.886-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[(4-methyl-1,3-thiazol-2- yl)methyl]nicotinamide Example 69 1,1-dimethyl-2-428 3.08 6-{5- hydroxypentylamine [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(2- hydroxy-1,1- dimethylpentyl)nicotinamideExample 70 2-trifluoromethylbenzylamine 472 3.38 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[2-(trifluoromethyl)benzyl]nicotinamide Example 71 2-chlorobenzylamine 4383.30 N-(2-chlorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamide Example 72 4-methylpiperidine 396 3.09N-cyclopropyl-3-fluoro-4- methyl-5-{5-[(4- methylpiperidin-1-yl)carbonyl]pyridin-2- yl}benzamide Example 73 N-isobutyl-N-methylamine384 3.02 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-isobutyl- N-methylnicotinamide Example 744-fluorobenzylamine 422 3.19 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(4- fluorobenzyl)nicotinamide Example 753,3-diethylazetidine 410 3.24 N-cyclopropyl-3-{5-[(3,3-diethylazetidin-1- yl)carbonyl]pyridin-2-yl}-5- fluoro-4-methylbenzamideExample 76 N-cyclopropyl-N-methylamine 396 3.06 N-cyclopentyl-6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-methylnicotinamide Example 77 N-ethyl-N-isopropylamine 384 2.98 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-ethyl-N-isopropylnicotinamide Example 78 2,3,4-trifluorobenzylamine 458 3.306-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2,3,4-trifluorobenzyl)nicotinamide Example 79 benzylamine 404 3.14N-benzyl-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamide Example 80 2-ethylpiperidine 410 3.17N-cyclopropyl-3-{5-[(2- ethylpiperidin-1- yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide Example 81 3-trifluoromethylbenzylamine 4723.40 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[3-(trifluoromethyl)benzyl]nicotinamide Example 822-ethyl-2-methylpiperidine 424 3.30 N-cyclopropyl-3-{5-[(2-ethyl-2-methylpiperidin-1- yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide Example 83 1,1-dimethylbutylamine 398 3.306-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(1,1-dimethylbutyl)nicotinamide Example 84 4-chloro-2-fluorobenzylamine 4563.37 N-(4-chloro-2- fluorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}nicotinamide Example 853,3,3-trifluoropropylamine 410 3.00 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(3,3,3- trifluoropropyl)nicotinamide Example86 4-trifluoromethylbenzylamine 472 3.41 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[4-(trifluoromethyl)benzyl]nicotinamide Example 87 3-methoxyaniline 4203.26 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3-methoxyphenyl)nicotinamide Example 88 4-methylaniline 404 3.34 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(4-methylphenyl)nicotinamide Example 89 3-fluorobenzylamine 422 3.20 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3-fluorobenzyl)nicotinamide Example 90 2-aminomethyl-5-methylfuran 4083.09 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-[(5- methyl-2- furyl)methyl]nicotinamide Example 913-methylaniline 404 3.36 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-(3- methylphenyl)nicotinamide Example 922,3-difluorobenzylamine 440 3.23 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(2,3- difluorobenzyl)nicotinamide Example 932,4-difluorobenzylamine 440 3.23 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(2,4- difluorobenzyl)nicotinamide Example 943-chloro-4-fluorobenzylamine 456 3.37 N-(3-chloro-4- fluorobenzyl)-6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}nicotinamideExample 95 4-methylbenzylamine 418 3.27 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(4-methylbenzyl)nicotinamide Example 96 3,4,5-trifluorobenzylamine 458 3.336-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3,4,5-trifluorobenzyl)nicotinamide Example 97 2-aminomethyl-3-methylthiophene424 3.21 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-[(3- methylthien-2- yl)methyl]nicotinamide Example 983-chloro-2,6-difluorobenzylamine 474 3.35 N-(3-chloro-2,6-difluorobenzyl)-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamide Example 99 (2-ethylcyclopropyl)methylamine 3963.24 6-{5- (Intermediate 39) [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-[(2- ethylcyclopropyl)methyl]nicotinamide Example 1002-propylpiperidine 424 3.33 N-cyclopropyl-3-fluoro-4- methyl-5-{5-[(2-propylpiperidin-1- yl)carbonyl]pyridin-2- yl}benzamide Example 1012-(2-aminoethyl)-4-methylthiazole 439 2.65 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[2-(4-methyl-1,3-thiazol-2- yl)ethyl]nicotinamide Example 1022-fluoro-2-phenylethylamine 436 3.07 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(2-fluoro- 2-phenylethyl)nicotinamideExample 103 2-(2-aminopropyl)thiazole 439 2.70 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-[1-methyl-2-(1,3-thiazol-2- yl)ethyl]nicotinamide Example 1042,4-dimethylpiperidine 410 3.07 N-cyclopropyl-3-{5-[(2,4-dimethylpiperidin-1- yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide Example 105 2,3-dimethylpiperidine 410 3.02N-cyclopropyl-3-{5-[(2,3- dimethylpiperidin-1-yl)carbonyl]pyridin-2-yl}-5- fluoro-4-methylbenzamide Example 1063-methylbut-2-enylamine 382 2.97 6-{5- [(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyl}-N-(3- methylbut-2- enyl)nicotinamide Example107 N-methyl-N-(1- 410 3.14 6-{5- methylcyclopentyl)amine[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-methyl-N- (1-methylcyclopentyl)nicotinamide Example 108 N-(2-cyclopentylethyl)-N- 4243.26 N-(2-cyclopentylethyl)-6- methylamine {5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-methylnicotinamide Example 109 1,1-dimethylbut-2-enylamine 396 3.066-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-[(2E)-1,1- dimethylbut-2- enyl]nicotinamide Example 1102,2-dimethyl-3-methyl-pyrrolidine 410 3.07 N-cyclopropyl-3-fluoro-4-methyl-5-{5-[(2,2,3- trimethylpyrrolidin-1- yl)carbonyl]pyridin-2-yl}benzamide Example 111 3-ethylpiperidine 410 3.10N-cyclopropyl-3-{5-[(3- ethylpiperidin-1- yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide Example 112 2-methyl-3,3,3,- 424 3.00 6-{5-trifluoropropylamine [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}-N-(3,3,3- trifluoro-2- methylpropyl)nicotinamide Example113 1-ethyl-1-methylpropylamine 398 3.15 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(1-ethyl- 1-methylpropyl)nicotinamide Example 114 2-methylpiperidine 396 2.90N-cyclopropyl-3-fluoro-4- methyl-5-{5-[(2- methylpiperidin-1-yl)carbonyl]pyridin-2- yl}benzamide Example 115 3,3,-dimethylpiperidine410 3.04 N-cyclopropyl-3-{5-[(3,3- dimethylpiperidin-1-yl)carbonyl]pyridin-2-yl}-5- fluoro-4-methylbenzamide Example 1163-methylpiperidine 396 2.95 N-cyclopropyl-3-fluoro-4- methyl-5-{5-[(3-methylpiperidin-1- yl)carbonyl]pyridin-2- yl}benzamide Example 117N-cyclohexyl-N-ethylamine 424 3.18 N-cyclohexyl-6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-ethylnicotinamide Example 118 ethylamine 342 2.58 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-ethylnicotinamide Example 119 N-isopropyl-N-methylamine 370 2.72 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-isopropyl-N-methylnicotinamide Example 120 3-hydroxy-1-methylpentylamine 414 2.886-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2-hydroxy-1- methylpentyl)nicotinamide Example 121 2-fluorobenzylamine 4223.18 6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(2-fluorobenzyl)nicotinamide Example 122 3-methylbenzylamine 418 3.27 6-{5-[(cyclopropylamino)carbonyl]- 3-fluoro-2- methylphenyl}-N-(3-methylbenzyl)nicotinamide Example 123 cyclopentylmethylamine 396 3.23N-(cyclopentylmethyl)-6-{5- [(cyclopropylamino)carbonyl]- 3-fluoro-2-methylphenyl}nicotinamideAbbreviations

-   DCM Dichloromethane-   DIPEA N,N-Diisopropylethylamine-   DME Dimethoxyethane-   DMF Dimethylformamide-   DMSO Dimethylsulphoxide-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybelizotriazole hydrate-   SPE bond-elut (solid phase extraction column)

The activity of the compounds of the invention as p38 inhibitors may bedemonstrated in the following assays:

p38 Kinase Assay

The peptide substrate used in the p38 assay wasbiotin-IPTSPITTTYFFFRRR-amide. The p38 and MEK6 proteins were purifiedto homogeneity from E. coli expression systems. The fusion proteins weretagged at the N-terminus with Glutathione-S-Transferase (GST). Themaximum activation was achieved by incubating 20 μL of a reactionmixture of 30 nM MEK6 protein and 120 nM p38 protein in the presence of1.5 uM peptide and 10 mM Mg(CH₃CO₂)₂ in 100 mM HEPES, pH 7.5, added to15 uL of a mixture of 1.5 uM ATP with 0.08 uCi[g-³³P]ATP, with orwithout 15 uL of inhibitor in 6% DMSO. The controls were reactions inthe presence (negative controls) or absence (positive controls) of 50 mMEDTA. Reactions were allowed to proceed for 60 min at room temperatureand quenched with addition of 50 uL of 250 mM EDTA and mixed with 150 uLof Streptavidin SPA beads (Amersham) to 0.5 mg/reaction. The DynatechMicrofluor white U-bottom plates were sealed and the beads were allowedto settle overnight. The plates were counted in a Packard TopCount for60 seconds. IC₅₀ values were obtained by fitting raw data to %I=100*(1−(I-C₂)/(C₁-C₂)), where I was CPM of background, C1 was positivecontrol, and C₂ was negative control.

αP38 Fluorescence Polarisation Method

αP38 was prepared in house. SB4777790-R Ligand was diluted in HEPEScontaining MgCl₂, CHAPS, DTT and DMSO. This was added to blank wells ofa Black NUNC 384 well plate. αP38 was added to this ligand mixture thenadded to the remainder of the 384 well plate containing controls andcompounds. The plates were read on an LJL Analyst and FluorescenceAnisotropy used to calculate the compound inhibition.

Results

The compounds described in the Examples were tested as described aboveand had IC₅₀ values of <10 μM.

1. (canceled)
 2. The process according to claim 13 wherein R¹ isselected from C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₇cycloalkyl optionallysubstituted by one or more C₁₋₆alkyl groups, phenyl optionallysubstituted by up to three substituents selected from R⁵ and R⁶,heteroaryl optionally substituted by up to three substituents selectedfrom R⁵ and R⁶.
 3. The process according to claim 13 wherein R² ishydrogen.
 4. The process according to claim 13 wherein R³ is methyl. 5.The process according to claim 13 wherein X is fluorine.
 6. The processaccording to claim 13 wherein R⁷ is selected from C₁₋₆alkyl,—(CH₂)_(q)—C₃₋₇cycloalkyl, trifluoromethyl, —(CH₂)_(r)heteroaryloptionally substituted by R¹³ and/or R¹⁴, and —(CH₂)_(r)phenyloptionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand/or heteroaryl optionally substituted by one or more R¹⁴ groups. 7.The process according to claim 13 wherein R⁸ is selected fromC₃₋₇cycloalkyl, CONHR⁹, heteroaryl optionally substituted by R¹³ and/orR¹⁴, and phenyl optionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand/or heteroaryl optionally substituted by one or more R¹⁴ groups. 8.The process according to claim 13 as defined in any one of Examples 1 to123. 9-12. (canceled)
 13. A process for preparing a compound of formula(I)

wherein R¹ is selected from hydrogen C₁₋₆alkyl optionally substituted byup to three groups selected from C₁₋₆alkoxy, halogen and hydroxy,C₂₋₆alkenyl C₃₋₇cycloalkyl optionally substituted by one or moreC₁₋₆alkyl groups, phenyl optionally substituted by up to three groupsselected from R⁵ and R⁶, and heteroaryl optionally substituted by up tothree groups selected from R⁵ and R⁶, R² is selected from hydrogen,C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one ormore C₁₋₆alkyl groups or (CH₂)_(m)R¹ and R², together with the nitrogenatom to which they are bound, form a four- to six-membered heterocyclicring optionally substituted by up to three C₁₋₆alkyl groups; R³ ischloro or methyl; R⁴ is the group —NH—CO—R⁷ or —CO—NH—(CH₂)_(q)—R⁸. R⁵is selected from C₁₋₆alkyl C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰—NHCOR¹⁰, —SO₂NHR⁹, —(CH₂)_(s)NHSO₂R¹⁰ halogen CN, OH,—(CH₂)_(s)NR¹¹R¹², and trifluoromethyl; R⁶ is selected from C₁₋₆alkylC₁₋₆alkoxy, halogens trifluoromethyl and —(CH₂)_(s)NR¹¹R¹²; R⁷ isselected from hydrogen, C₁₋₆alkyl —(CH₂)_(q)—C₃₋₇cycloalkyl optionallysubstituted by one or more C₁₋₆alkyl groups, trifluoromethyl,—(CH₂)_(r)heteroaryl optionally substituted by R¹³ and/or R¹⁴, and—(CH₂)_(r)phenyl optionally substituted by R¹³ and/or R¹⁴; R⁸ isselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl optionally substitutedby one or more C₁₋₆alkyl groups, CONHR⁹, phenyl optionally substitutedby R¹³ and/or R¹⁴, and heteroaryl optionally substituted by R¹³ and/orR¹⁴; R⁹ and R¹⁰ are each independently selected from hydrogen andC₁₋₆alkyl, or R⁹ and R¹⁰, together with the nitrogen atom to which theyare bound, form a five- to six-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁵, wherein the ring may be substituted by up to two C₁₋₆alkylgroups; R¹¹ is selected from hydrogen, C₁₋₆alkyl and—(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or moreC₁₋₆alkyl groups, R¹² is selected from hydrogen and C₁₋₆alkyl, or R¹¹and R¹², together with the nitrogen atom to which they are bound, form afive or six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen sulfur and N—R¹⁵; R¹³ isselected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰—NHCOR¹⁰, halogen, CN, —(CH₂)_(s)NR¹¹R¹², trifluoromethyl, phenyloptionally substituted by one or more R¹⁴ groups and heteroaryloptionally substituted by one or more R¹⁴ groups; R¹⁴ is selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halogen trifluoromethyl and —NR¹¹R¹²; R¹⁵ isselected from hydrogen and methyl; X and Y are each independentlyselected from hydrogen methyl and halogen; Z is halogen; m is selectedfrom 0, 1, 2, 3 and 4, wherein each carbon atom of the resulting carbonchain may be optionally substituted with up to two groups selectedindependently from C₁₋₆alkyl and halogen; n is selected from 0, 1 and 2;q is selected from 0, 1 and 2; r is selected from 0 and 1; and s isselected from 0, 1, 2 and
 3. which comprises (a) reacting a compound of(II)

in which R¹, R², Z, m and n are as defined in Formula (I) and W ishalogen, with a compound of formula (III)

in which R³, R⁴, X and Y are as defined in Formula (I), in the presenceof a catalyst, or (b) reacting a compound of formula (VIII)

with a compound of formula (III) as hereinbefore defined and thenreacting the acid thus formed with an amine of formula (V)

in which R¹, R² and m are as defined in Formula (I), under amide formingconditions, or (c) reacting a compound of formula (II) as hereinbeforedefined with a compound of formula (IX)

in which R³, R⁴, X and Y are as defined in Formula (I), in the presenceof a catalyst.
 14. A compound of the formula:

in which R³, R⁴, X and Y are as defined in Formula (I), X and Y are eachindependently selected from hydrogen, methyl and halogen; R³ is chloroor methyl; R⁴ is the group —NH—CO—R⁷ or —CO—NH—(CH₂)_(q)—R⁸; R⁷ isselected from hydrogen, C₁₋₆alkyl, —(CH₂)_(q)—C₃₋₇cycloalkyl optionallysubstituted by one or more C₁₋₆alkyl groups, trifluoromethyl,—(CH₂)_(r)heteroaryl optionally substituted by R¹³ and/or R¹⁴, and—(CH₂)_(r)phenyl optionally substituted by R¹³ and/or R¹⁴; R⁸ isselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl optionally substitutedby one or more C₁₋₆alkyl groups, CONHR⁹, phenyl optionally substitutedby R¹³ and/or R¹⁴, and heteroaryl optionally substituted by R¹³ and/orR¹⁴; R⁹ and R¹⁰ are each independently selected from hydrogen andC₁₋₆alkyl, or R⁹ and R¹⁰, together with the nitrogen atom to which theyare bound, form a five- to six-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁵, wherein the ring may be substituted by up to two C₁₋₆alkylgroups; R¹¹ is selected from hydrogen, C₁₋₆alkyl and—(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or moreC₁₋₆alkyl groups, R¹² is selected from hydrogen and C₁₋₆alkyl, or R¹¹and R¹², together with the nitrogen atom to which they are bound, form afive or six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵; R¹³ isselected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰,—NHCOR¹⁰, halogen, CN, —(CH₂)_(s)NR¹¹R¹², trifluoromethyl, phenyloptionally substituted by one or more R¹⁴ groups and heteroaryloptionally substituted by one or more R¹⁴ groups; R¹⁴ is selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl and —NR¹¹R¹²; R¹⁵ isselected from hydrogen and methyl; Z is halogen; m is selected from 0,1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chainmay be optionally substituted with up to two groups selectedindependently from C₁₋₆alkyl and halogen; n is selected from 0, 1 and 2;q is selected from 0, 1 and 2; r is selected from 0 and 1; and s isselected from 0, 1, 2 and
 3. 15. The compound according to claim 14wherein R³ is methyl.
 16. The compound according to claim 14 wherein Xis halogen and Y is hydrogen.
 17. The compound according to claim 14wherein R⁴ is —CO—NH—(CH₂)_(q)—R⁸.
 18. The compound according to claim17 wherein R⁸ is selected from C₃₋₇cycloalkyl, CONHR⁹, heteroaryloptionally substituted by R¹³ and/or R¹⁴, and phenyl optionallysubstituted by C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl,—CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN, trifluoromethyl, phenyl optionallysubstituted by one or more R¹⁴ groups and/or heteroaryl optionallysubstituted by one or more R¹⁴ groups.
 19. The compound according toclaim 17 wherein q is
 0. 20. The compound according to claim 17 whereinR⁸ is a C₃₋₇cycloalkyl.
 21. The compound according to claim 20 whereinR⁸ is a cyclopropyl, q is 0, R³ is methyl, and X is halogen.
 22. Thecompound according to claim 21 wherein X is fluorine.
 23. A compound ofthe formula:

wherein W is halogen; Z is halogen; R¹ is selected from hydrogen,C₁₋₆alkyl optionally substituted by up to three groups selected fromC₁₋₆alkoxy, halogen and hydroxy, C₂₋₆alkenyl, C₃₋₇cycloalkyl optionallysubstituted by one or more C₁₋₆alkyl groups, phenyl optionallysubstituted by up to three groups selected from R⁵ and R⁶, andheteroaryl optionally substituted by up to three groups selected from R⁵and R⁶, R² is selected from hydrogen, C₁₋₆alkyl and—(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or moreC₁₋₆alkyl groups, or (CH₂)_(m)R¹ and R², together with the nitrogen atomto which they are bound, form a four- to six-membered heterocyclic ringoptionally substituted by up to three C₁₋₆alkyl groups; R⁵ is selectedfrom C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl optionallysubstituted by one or more C₁₋₆alkyl groups, —CONR⁹R¹⁰, —NHCOR¹⁰,—SO₂NHR⁹, —(CH₂)_(s)NHSO₂R¹⁰, halogen, CN, OH, —(CH₂)_(s)NR¹¹R¹², andtrifluoromethyl; R⁶ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen,trifluoromethyl and —(CH₂)_(s)NR¹¹R¹²; R⁹ and R¹⁰ are each independentlyselected from hydrogen and C₁₋₆alkyl, or R⁹ and R¹⁰, together with thenitrogen atom to which they are bound, form a five- to six-memberedheterocyclic ring optionally containing one additional heteroatomselected from oxygen, sulfur and N—R¹⁵, wherein the ring may besubstituted by up to two C₁₋₆alkyl groups; R¹¹ is selected fromhydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substitutedby one or more C₁₋₆alkyl groups, R¹² is selected from hydrogen andC₁₋₆alkyl, or R¹¹ and R¹², together with the nitrogen atom to which theyare bound, form a five or six-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁵; R¹⁵ is selected from hydrogen and methyl; m is selected from 0,1, 2, 3 and 4, wherein each carbon atom of the resulting carbon chainmay be optionally substituted with up to two groups selectedindependently from C₁₋₆alkyl and halogen; n is selected from 0, 1 and 2;q is selected from 0, 1 and 2; and s is selected from 0, 1, 2 and
 3. 24.The compound according to claim 23 wherein R¹ is selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₇cycloalkyl optionally substituted by one ormore C₁₋₆alkyl groups, phenyl optionally substituted by up to threesubstituents selected from R⁵ and R⁶, heteroaryl optionally substitutedby up to three substituents selected from R⁵ and R⁶.
 25. The compoundaccording to claim 24 wherein R¹ is selected from a methyl, ethyl,n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 1-ethyl-1-methyl-propyl, n-butyl, isobutyl,3-methylbutyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl,2-pentyl or 1-methylpentyl,
 26. The compound according to claim 23wherein R² is hydrogen.
 27. The compound according to claim 23 whereinR¹ is a 2,2,dimethylpropyl, R² is hydrogen, and n is
 0. 28. The compoundaccording to claim 27 wherein W is chlorine.
 29. A compound of theformula:

X and Y are each independently selected from hydrogen, methyl andhalogen; R³ is chloro or methyl; R⁴ is the group —NH—CO—R⁷ or—CO—NH—(CH₂)_(q)—R⁸; R⁷ is selected from hydrogen, C₁₋₆alkyl,—(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or moreC₁₋₆alkyl groups, trifluoromethyl, —(CH₂)_(r)heteroaryl optionallysubstituted by R¹³ and/or R¹⁴, and —(CH₂)_(r)phenyl optionallysubstituted by R¹³ and/or R¹⁴; R⁸ is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl optionally substituted by one or more C₁₋₆alkyl groups,CONHR⁹, phenyl optionally substituted by R¹³ and/or R¹⁴, and heteroaryloptionally substituted by R¹³ and/or R¹⁴; R⁹ and R¹⁰ are eachindependently selected from hydrogen and C₁₋₆alkyl, or R⁹ and R¹⁰,together with the nitrogen atom to which they are bound, form a five- tosix-membered heterocyclic ring optionally containing one additionalheteroatom selected from oxygen, sulfur and N—R¹⁵, wherein the ring maybe substituted by up to two C₁₋₆alkyl groups; R¹¹ is selected fromhydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substitutedby one or more C₁₋₆alkyl groups, R¹² is selected from hydrogen andC₁₋₆alkyl, or R¹¹ and R¹², together with the nitrogen atom to which theyare bound, form a five or six-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁵; R¹³ is selected from C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted by one or moreC₁₋₆alkyl groups, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN, —(CH₂)_(s)NR¹¹R¹²,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand heteroaryl optionally substituted by one or more R¹⁴ groups; R¹⁴ isselected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl and—NR¹¹R¹²; R¹⁵ is selected from hydrogen and methyl; Z is halogen; m isselected from 0, 1, 2, 3 and 4, wherein each carbon atom of theresulting carbon chain may be optionally substituted with up to twogroups selected independently from C₁₋₆alkyl and halogen; n is selectedfrom 0, 1 and 2; q is selected from 0, 1 and 2; r is selected from 0 and1; and s is selected from 0, 1, 2 and
 3. 30. The compound according toclaim 29 wherein R³ is methyl.
 31. The compound according to claim 29wherein X is halogen and Y is hydrogen.
 32. The compound according toclaim 29 wherein R⁴ is —CO—NH—(CH₂)_(q)—R⁸.
 33. The compound accordingto claim 32 wherein R⁸ is selected from C₃₋₇cycloalkyl, CONHR⁹,heteroaryl optionally substituted by R¹³ and/or R¹⁴, and phenyloptionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁹R¹⁰, —NHCOR¹⁰, halogen, CN,trifluoromethyl, phenyl optionally substituted by one or more R¹⁴ groupsand/or heteroaryl optionally substituted by one or more R¹⁴ groups. 34.The compound according to claim 33 wherein R⁸ is a C₃₋₇cycloalkyl. 35.The compound according to claim 34 wherein q is
 0. 36. The compoundaccording to claim 33 wherein R⁴ is —CO—NH—(CH₂)_(q)—R⁸, R⁸ is acyclopropyl, q is 0, R³ is methyl, and X is halogen.
 37. The compoundaccording to claim 36 wherein X is fluorine.
 38. The compound accordingto claim 29 wherein X is fluorine.